After the opening logos, the screen cuts to the middle of the ocean, where a small sailboat is seen drifting across the mad waves during a large thunderstorm. In the boat are two sailors. One of the sailors drops a giant net into the ocean, which picks up a large pot with an octopus inside. As the sailors attempt to pull the octopus up, a young Flippy, getting chased by his bullies, ends up getting chased straight into the pot as it reaches the surface. After the sailors take off the net, the octopus quickly goes back into the water, leaving only Flippy in the pot. After the sailors see Flippy, they unanimously agree to give Flippy to the nearby pet store, Penelope's Pets. As they sail away to shore, Flippy realizes everything. He might never see his home again, and his last memory of home was getting bullied. It began to aggravate him. Lightning strikes as the logo of the film, "Dog Man 2," appears.
Years later, after the events of the previous movie, we see Dog Man heading to work, with Li'l Petey eating breakfast. Li'l Petey tells Dog Man to have fun at work, as Dog Man heads into his cop car and drives throughout Ohkay City, in a similar way that Officer Knight and Greg the Dog did in the previous movie, however the wanted poster of Petey is replaced with Petey waving to Dog Man through the Cat Jail window. Dog Man stops at Jim's Bank and waits for a bit. Then, he silently counts to himself. Three, two, one. Just then, the bank's alarm starts sounding as two robbers with a lot of money head into a truck and start driving away from the bank. Dog Man smirks and starts chasing the robbers. The non-driving robber looks out the window and sees Dog Man. He gets angry and pulls out a gun, saying that they won't have to worry about Dog Man anymore as he jumps out the window, preparing to shoot Dog Man. However, just before he does so, he gets tased, forcing him to drop his gun and fall straight down into Dog Man's custom sunroof. Then, Dog Man grabs a walkie and barks into it, informing Chief that he needs backup. Chief says that they're on their way as a ton of police cars start driving in front of the robber, forcing him to turn around, where Dog Man would park his car, get out of it, and jump straight into the truck's driver window, knocking out the driver, and parking the truck.
As a few other cops start handcuffing and sending the robbers to jail, Milly starts talking to Dog Man about what kind of gift he was going to give to Chief. Dog Man gets confused, and Milly tells him that it was Chief's birthday tomorrow. She also says she got him Supa Brain Dots. Dog Man is shocked at the news and sprints back home, where he starts panicking about the perfect gift for his boss. After a bit of questioning what he should give Chief, Li'l Petey sees him and mentions the idea about a pet for Chief since he didn't seem to have any company at all. Dog Man hears this and gets relieved as he goes out to Penelope's Pets. There, he sees all of the dog toys and other things designed for dogs and gets extremely happy and plays with everything. Eventually, two workers come in and get shocked at the mess Dog Man made. The male worker reluctantly gets a mop and starts cleaning everything up, while the female worker talks to Dog Man, eventually bringing up the idea for the perfect pet: a fish. Dog Man agrees and is led to the fish area. Dog Man looks through all the fish and concludes he wanted a dead fish. The female worker snorts and mocks him for wishing to roll around in it. Dog Man then realizes that while he loved to roll around in dead fish, Chief would just think of dead fish as gross. So, Dog Man looks around again. However, he can't seem to find the perfect fish. So, the female worker goes into a "storage closet" where she comes out and brings the most ev---perfect fish named Flippy. Dog Man thinks he was great and gets him. However, Dog Man realizes that he doesn't have any money. However, just before he can say anything, Sarah Hatoff comes into the pet store and buys Zuzu. However, before she leaves, she sees Dog Man and introduces herself to him before saying that she will pay for Flippy as well. After doing so, Dog Man thanks Sarah as they both leave.
The next day, Chief walks into the cop station to see everyone tell him happy birthday. Chief nearly cries and goes through his presents. Eventually, Dog Man gives Chief Flippy, as all the cops cheer for Chief, who was actually crying from Dog Man. Afterward, Chief puts Flippy on a stool and puts his can of Supa Brain Dots on a drawer near Flippy. He then noticed that it was lunchtime and slams the door to get lunch. This leads the Supa Brain Dots to fall into Flippy's fishbowl. Soon, Flippy becomes smarter and smarter and collects psychokinetic abilities, allowing him to create a disguise as he evilly laughs.
Meanwhile, in Cat Jail, Petey begins to devise a plan to escape jail since it was kind of boring, and he wanted to see his clone. He tries asking help from other inmates from Cat Jail, though they all refuse to help Petey after the last time he escaped jail and left them to rot in Cat Jail. Eventually, Big Jim does agree to help Petey and goes outside with him in the jailyard, where Petey sits on a seesaw. Big Jim sees this and grins as he sits down on the other side of the seesaw, catapulting Petey above the fence and into freedom. Petey states that he didn't even mean for that to happen, but he still leaves the facility to look for Li'l Petey.
Meanwhile, at Jim's Bank, Kinney greets a new customer into the bank and asks him if he needs anything today. The customer is revealed to be Flippy in disguise, who has Kinney turn upside down. Flippy tells him that the only thing he needed was all the money in the bank. Kinney fearfully starts putting tens of hundreds of dollars inside multiple moneybags and gives them all to Flippy. After Kinney does so, Flippy has Kinney fly through the bank as he leaves. A nearby Sarah sees this and tells Roscoe to start filming. Roscoe does so, and soon, the news of the bank robbery goes through to the cops and Li'l Petey. Dog Man and Chief start driving to Jim's Bank and start following Flippy. However, their cop car starts flying, forcing Chief and Dog Man to get out through the windows of the car. Chief questions how that was possible before he starts flying away. Just then, Petey ran into the fight behind Flippy, while Li'l Petey ran into the fight in front of Flippy. Li'l Petey started to fly behind Flippy, landing right in front of a running Petey. Li'l Petey notices Petey and says hi. Petey, seeing this, gets extremely angry at Flippy and tackles him, taking off his disguise to reveal Flippy. Everyone gets confused as to how Flippy was the robber. However, Petey, still aggravated, takes Flippy from his fishbowl and puts him in his mouth. Everyone tells Petey to spit him out, which Petey reluctantly does. Doing this ultimately suffocated Flippy since he couldn't breathe in air, ultimately killing him. Petey looks around, smirks, and attempts to eat Flippy again, though Chief yells to spit him back out, which Petey reluctantly does.
After fighting Flippy, everyone gathers around to figure out what to do now that Flippy died. Sarah brings up that they needed to figure out how Flippy has psychokinetic powers in the first place. Petey agrees and tells everyone that he would experiment on Flippy to figure out how he got his powers. Just then, they hear the sound of bones cracking and look to find that Dog Man had been rolling around Flippy's corpse ever since they started talking. Petey wonders what to do now that Flippy was destroyed. However, Li'l Petey tells them that all they had to do was replace Flippy's bones with technology. Petey likes the idea and asks Dog Man if he can have Li'l Petey for the night to help with his studies. Dog Man whines, which gives Petey the idea to shout for 80-HD. 80-HD quickly flies in, and Petey tells Dog Man he can have 80-HD for the night. Dog Man reluctantly agrees.
Around an hour later, we see Petey working on Flippy and turning him into a cyborg fish with the help of Li'l Petey. After finishing, they take out his brain and study it, learning that Flippy got his powers from accidentally eating an entire jar-full of Supa Brain Dots in one sitting. Li'l Petey finds that the Supa Brain Dots contained a chemical called "Gr²," which in high doses causes supa anger, making them believe that was why Flippy was evil, and they needed to get rid of Supa Brain Dots. Afterward, Petey sends Li'l Petey back to Dog Man's house, where Dog Man and 80-HD were dancing and playing air guitars while rock music was being played. They see Petey and Li'l Petey, and Petey tells Dog Man he can keep 80-HD with him and Li'l Petey. Dog Man and 80-HD high-five each other joyfully. Then, Petey explains to Dog Man that he had to pick up every Supa Brain Dot in the city so nothing else happened, like with Flippy. Dog Man salutes Petey and runs out to start doing so.
A montage in Flip-o-Rama pursues of Dog Man collecting every Supa Brain Dot in Ohkay City, and after a long time, Dog Man finally finishes and gives the wagon of Supa Brain Dots to Chief. Chief thanks Dog Man and asks him if he can get Flippy's body so he can keep it nice and safe. Dog Man agrees to go get it from Petey, and after getting it from Petey, he accidentally trips, dropping Flippy into a nearby sewage opening. Dog Man panics after doing so and runs away. However, while Dog Man ran away, we see Flippy going through the sewage current and getting picked up by a mysterious figure.
The next day, Dog Man walks into the cop station to tell Chief the bad news. Chief goes ballistic that Flippy had been lost and yells at Dog Man to get out of the station and to go home. Dog Man gloomily does so. At home, he finds out that Petey and Li'l Petey were having fun together through a note. Dog Man gets even more saddened after seeing this and asks 80-HD to get a plant he can hide behind. 80-HD does so, and Dog Man lies down. 80-HD, feeling bad for Dog Man, lies down with him, cheering Dog Man up a little.
Meanwhile, Flippy is awoken to find that he was in a mysterious location and had robotic parts now. Flippy is confused as to what had happened. However, just then, the man who had picked up Flippy comes in, revealing the man to be none other than Dr. Scum. Dr. Scum reveals that, even though he didn't know why Flippy was a cyborg, he did know that he revived Flippy using Living Spray, one of his most popular inventions alongside Invisible Spray, Obey Spray, and the hit new Sustain Spray. Dr. Scum tells Flippy about the Supa Brain Dots in the cop station that was able to create an army of psychokinetic people. Flippy is intrigued at this and starts coming up with a plan with all of Dr. Scum's sprays. He then takes a can of Invisible Spray and Obey Spray. Dr. Scum asks what he was doing, which Flippy reveals that he would make an army of people just like him with the Supa Brain Dots and would use the Obey Spray to make them obey his every command. Dr. Scum gets mad and says that he was supposed to be with him, making Flippy annoyed. Just then, the can of Sustain Spray started flying and shaking, as it opened its own lid and sprayed Dr. Scum. Flippy then mocks Dr. Scum about the spray after reading the instructions and finding out that whatever was sprayed with it would be in the exact position it was sprayed with for up to 48 hours. Flippy smirks and leaves with the Invisible Spray and Obey Spray.
As soon as Flippy leaves the lab, he immediately sprays himself and the Obey Spray with Invisible Spray and tosses away the Invisible Spray. He heads toward the cop station, where the Mean Cop is guarding the Supa Brain Dots. Flippy yells out, "Boo!", frightening the Mean Cop. Flippy then takes the Supa Brain Dots and leaves, hoping to find somewhere where he can create an army. He then comes across a pond, where multiple tadpoles are being taught by their mother about life. Just then, the tadpoles' mother starts flying away into the sky, as Flippy splashes himself with the pond water to reveal himself. He tells the tadpoles that their mom wanted to have a trip in space and he would be their babysitter. He then drops all the Supa Brain Dots in the pond, collects the Obey Spray, and sprays the whole pond, turning the tadpoles into mindless, psychokinetic slaves. Flippy laughs evilly as he had finally created an army capable of destroying the multiverse.
Soon enough, half the city gets destroyed by the brainwashed tadpoles, which goes over the news to the cops and Dog Man and 80-HD. They soon head to the tadpoles with butterfly nets and each attempt to grab a tadpole. However, they all start flying and get caught in the nets. Just as they do so, Dog Man realizes that the tadpoles were being brainwashed by someone, and as he points it out to everyone, Flippy reveals himself and tells them how Dr. Scum revived him with Living Spray. Chief angrily tells Dog Man that he knew something would've happened when he accidentally dropped Flippy in the sewers, making Dog Man feel guilty. Sarah starts calling for help and remembers her pet poodle Zuzu, who was in her purse that hadn't been caught yet. Sarah tells Zuzu to go get help, which Zuzu complies with and starts sprinting toward Petey and Li'l Petey's lab.
Soon, Zuzu came into Petey and Li'l Petey's lab and started barking, attempting to tell them everything. Petey and Li'l Petey agree to help as they grab everything they can in the lab. They end up grabbing the costumes that were in Dog Man and Cat Kid and start sprinting towards the battle alongside Zuzu. Eventually, they reach the battle, where Petey heads to one side of the tadpoles, while Li'l Petey goes to the other. Petey ends up getting captured, and Li'l Petey nearly gets captured by a female tadpole and, out of self-defense, takes his claws out, scaring the female tadpole. Li'l Petey apologizes for scaring her and says he wasn't going to actually slice her, comforting her a little. The tadpole starts to head back with the other tadpoles. However, Li'l Petey stops her and tells her that she didn't really want to conquer the multiverse and was just brainwashed into doing so. The tadpole laughs at the thought, which ends up erasing her need to obey Flippy. She starts to realize that she didn't actually want to be with Flippy and just wanted to be with her mom and all her siblings. Li'l Petey tells her that they were going to defeat Flippy and erase the need to obey him to everyone, allowing her to be with her family. She agrees, and the two run away. As they do, they introduce each other as Li'l Petey and Molly.
As they reach Petey's lab, they come across a super computer, who was able to solve any problem ever. They ask it how to make an antidote for Supa Brain Dots and Obey Spray, which it gives the ingredients to. After a while, they end up finishing it and devise a plan to trick everyone to lose their powers as they grab a balloon. They start running back to the chaos, where Flippy notices Molly out of line, stops her, and asks why she wasn't with the rest of her siblings. She lies that she was attempting to stop Li'l Petey from popping his balloon that would release an antidote for Obey Spray and Supa Brain Dots. Flippy smirks as he uses his powers to grab the balloon from Li'l Petey. Before he does so, he tells all of the tadpoles to go into the pond and not breathe into the air so that they didn't breathe in the antidote. However, once they get in, Li'l Petey, with the actual antidote, starts pouring it in, turning the tadpoles back to normal. Molly sees this and blows a raspberry at Flippy as she escapes Flippy's grasp and releases everyone from their nets, which were still in the air due to Flippy's powers. Everyone thanks Li'l Petey for everything he and Molly did before they get to Flippy.
Flippy becomes more angry than he ever had been before and starts grabbing everyone and attempts to make them fly away. Everyone, except Li'l Petey. Li'l Petey comes in from behind Flippy and asks Flippy why he was so angry. Flippy says it was because they stopped him from conquering the multiverse. Li'l Petey asks why Flippy was attempting to conquer the multiverse. Flippy ponders the question and remembers why he became a villain. He reveals that when he was young, everybody bullied him except for his mother. Everything seemed to be okay until the bullying got worse, and the bullies chased him into a large pot, which brought him to the surface and left to take Flippy into the pet store. Since that moment, Flippy's last memory of his home was being bullied, and he never returned again. Li'l Petey says that he was sorry, and all it seemed he needed was a friend and volunteers to be his friend. Flippy, nearly in tears, thanks Li'l Petey and sets everyone free.
Dog Man quickly runs up to Flippy, handcuffs him, and takes him to his cop car. However, just before they leave, Li'l Petey remembers that Flippy was also a subject to Supa Brain Dots, so all of his crimes were under the influence of the supa anger. Dog Man ponders this and releases Flippy. Chief tells Flippy that he still needs to be punished and, therefore, would be placed in community service. Flippy agrees and asks Chief if his community service could be raising the tadpoles, now that their mom was nowhere to be found and they didn't have anyone except themselves. Chief agrees that would be his sentence, and Molly cheers after hearing she now had someone to take care of her.
Everyone leaves to go home after a long day. However, just before they leave, Petey tells Dog Man that he shouldn't have kept Li'l Petey for himself and comes up with the idea that he has Li'l Petey on the weekdays, and Dog Man and 80-HD had him on the weekends. Dog Man agrees to this, as they leave. While they do so, Sarah reveals to Petey that the public asked for him to be pardoned for his great help in defeating Flippy twice. Eventually, Dog Man and Li'l Petey arrive home, where 80-HD had set up a party for the three of them. Dog Man and Li'l Petey smirk at each other and start dancing, as the end credits start.