Dr. Octavius is a research scientist working under Norman Osborn at OsCorp. He is very timid and willing to apologize for every little thing, a direct contrast to his boss, Norman. He is one of OsCorp's most intelligent scientists and the creator of a four armed harness that makes him able to do dangerous experiments, playing a part in the creation of Sandman and Rhino.

Eventually, as the result of a devastating accident (orchestrated by the Green Goblin), his arms became permanently fused to his back and he was driven out of his mind, becoming the vengeful Dr. Octopus. He attacked his former employer, and then Spider-Man, blaming him for the accident which created him (believing Spider-Man to be acting out of his own desire to have revenge for Octavious' creation of the supervillains who attacked him). Spider-Man eventually defeated the menacing doctor at a Coney Island carnival.

In the following days, Doc Ock sent letters to Electro, who was going through therapy at Ravencroft. He convinced Electro to break him and the other members of the Sinister Six out of Ryker's Island to fight Spider-Man. Doc Ock showed an interest in Spider-Man's symbiote costume during the final battle at Central Park. Spider-Man's symbiote costume started to take control of Spider-Man and if it weren't for the intervention of Captain George Stacy, Doctor Octopus wouldn't have survived the battle.

He is later incarcerated at Ravencroft Asylum, alongside Electro. When Kraven comes to break both of them out, Octavius is seemingly cured, and regretful of his criminal past. Under the orders of the Master Planner, Tinkerer manipulates Octopus's tentacles to break out the apparently terrified doctor.

Doctor Octopus turns out to be the Master Planner himself, hiding in plain sight while he lets his minions prepare for his master plan. He orchestrates Gwen Stacy's kidnapping at the hands of Vulture and Electro, in order to manipulate George Stacy to obtain the secret codes from Homeland Security. His plans were interrupted after Spider-Man found his hideout. Upon being defeated, Doctor Octopus initiated the self-destruct sequence in his base and got away, though he is mentioned by his Master Planner alias in the following episode, seemingly having loaned the use of Sandman to the Big Man in exchange for a cut of his current job.

Doctor Octopus, now representing the increasingly-growing supervillain faction of New York's crime, attended the bidding for the Rhino chip, but curiously made no bid. It was later revealed he was more interested in its destruction (no doubt so he could continue to remain the only one to hire out Supervillains), and showed Rhino about the chip, manipulating him to destroy it when Roderick Kingsley wins the bid.

Later, Doctor Octopus went to the Valentine's Day summit to decide the crime scene in New York, accomponied by the Vulture. However, Octopus, along with Tombstone and Silvermane, were betrayed by Hammerhead, starting a three-way fight. Octopus fought Tombstone and Silvermane until the fight was broken up by the arrival of Spider-Man, who managed to defeat Octopus by knocking him out and stealing his power battery so his arms wouldn't work.

Though he was seen by witnesses fighting in 'Gangland', he was taken to Ravencroft. Which would explain his absence in the jail-break of Rykers in 'Opening Night'