Simon first appears when his henchman Cad Lackey brought to him a beagle named Shoeshine. Simon is vituperative and bitter against the mayor of Capitol City, who has turned down his proposal for a type of genetic experimenting for the city, and plans to prove him wrong by testing his new serum on the beagle. However, Shoeshine escapes and runs amok in the lab, causing a fire and accidentally becoming exposed to a variety of DNA concoctions and chemicals that Simon developed, which modifies his DNA and gives him the strength to break through the metal door to the lab. After witnessing his work's "success" Simon is stunned when a burning monitor falls onto him, and Cad rushes to his aid.
Simon then sends Cad to find Shoeshine. Later, Simon and Cad find a new lair beneath the city, then plan a robbery to get the funds they need to rebuild Simon's lab. Cad leads a band of thugs to rob a jewelry store, seen on the news by Shoeshine and Jack, who convinces Shoeshine to use his powers to save the hostages inside. Shoeshine consents, disguising himself with a fish kite so he won't be recognized, and saves the hostages, though Cad escapes with some of the stolen goods.
As Shoeshine, now named Underdog, becomes the hero of the city, Simon's attempts to recreate his serum are unsuccessful time and time again, so he sends Cad to try and obtain a sample of Underdog's DNA, hoping to use it to recreate the serum. Cad's attempt to capture Underdog goes unsuccessful, but he does manage to obtain his collar, which has his name and address on it. Simon and Cad go to the house and kidnap Dan, making him believe they have Jack to subdue him, and force him to call for Underdog for help. Underdog quickly hears Dan's cries, and he and Jack go to rescue him, only for Simon to use both Jack and Dan as hostages to convince Underdog to give up his DNA. Not wanting his family to be hurt, Underdog complies, and Barsinister makes a whole jar full of pills that contain Underdog's super powers. Simon convinces Underdog to take an antidote pill, turning him back into a normal beagle, then feeds the super pills to three German Shepherds he obtained and trained. He and Cad leave the family trapped in the sewers, but thanks to Dan's experience from the police force, he is able to set everyone free and they take off after Barsinister with a hypodermic filled with the super power antidote.
Simon takes the Mayor hostage in city hall and instructs Cad to attach a bomb rigged with a mind control serum to the roof of the building. Molly and Polly follow Cad after witnessing him head through the service entrance. Underdog, meanwhile, smells the bomb Cad is carrying, at first doubting his nose, but decides to trust his instincts and heads inside the capitol building despite being powerless to confront Simon. During a short struggle (in which the mayor is knocked unconscious), Underdog accidentally rips open Simon's pocket, gaining access to the super pills and eating one, getting his powers back. He does battle with the three German Shepherds, whom he temporarily incapacitates after hearing Polly and Molly in danger, as they were captured by Cad and tied to the roof of the building beside the bomb. Enraged with Underdog's return to foil his plan, Simon eats one of the super pills and gains super powers himself, fighting Underdog until he distracts him with one of his natural instincts; chasing a Frisbee, which is actually a giant iron shield from a statue. Underdog is knocked down long enough for the German Shepherds to recover, but he convinces them that Simon isn't a good master by pointing out Simon's mistreatment of them (not even giving them real names). The German Shepherds turn on Simon, realizing their role is as man's best friend, not man's best slave, and restrain him with their strength while Shoeshine rushes to disarm the bomb.
The Mayor regains consciousness and stumbles outside, allowing Dan through the police barricade to deal with Simon by injecting the antidote into him.
Afterwards, Simon Bar Sinister and his henchman Cad are sent to jail for their crimes.