In the Ultimate Marvel Universe, Norman Osborn is a corrupt industrialist and scientist who is trying to perfect the Super Soldier drug for S.H.I.E.L.D., an obsession that leads to the neglect of his wife and son, Harry. In Ultimate Spider-Man #1, an OZ-injected spider bites Peter Parker on a field trip. Peter develops amazing powers, and Norman theorizes that if the OZ combined with spider DNA gave Parker the abilities of a spider, then if Norman were to receive OZ combined with his own DNA, he could become a heightened version of himself. The experiment goes wrong and an explosion occurs, affecting Harry and Dr. Otto Octavius.

Norman, however, is transformed into a muscular, grotesque, demonic-looking monster, granting him superhuman strength, reflexes, stamina and durability, and enabling him to leap great distances. He is also pyrokinetic, as he can throw flaming balls of destructive energy and (in the Ultimate Spider-Man video game) surround himself with flames. In an attempt to destroy all evidence of his existence, the Goblin kills Norman's wife and attempts to kill Harry, who manages to escape while the house is burning down. The next day, he attacks Harry's school but is stopped by Spider-Man. During the fight, the Goblin plummets off a bridge into the river, seemingly dead. However, Norman survives and has, in his words, "evolved". He can now control his transformations into an intelligent incarnation of the "Green Goblin" via OZ injections. Due to overdosing on OZ, Osborn suffers from hallucinations. These include seeing everything through a blood-red filter, objects such as the Spider on Spider-Man's chest moving around, and creatures called "plasmids" tormenting him.

Taking Harry back, Norman moves back into the city, blaming rival Justin Hammer for the explosion. Under the spell of the Goblin, he reveals himself to Parker, telling him to give up the life as Spider-Man and work for him, or suffer the deaths of Parker's loved ones. The Goblin tells Parker to kill Nick Fury, the Head of S.H.I.E.L.D. When Parker refuses, the Goblin kidnaps Mary Jane Watson, Peter's girlfriend, and attempts to kill her by hurling her from the top of a bridge. Spider-Man is able to save Mary Jane, and joins S.H.I.E.L.D. operatives in attacking Osborn. The battle continues at Osborn's Manhattan penthouse, where the Goblin transforms even further after taking several more OZ injections and begins to choke the life out of Parker. Harry discovers the scene, picking up a shattered window pane and jamming it into his father's back, reverting him to his human self. Norman is taken into custody by S.H.I.E.L.D.

In the Ultimate Six limited series, the Goblin and his old assistant, Dr. Octavius, devise a plan to escape from prison which uses Norman's new ability to transform into his demon form at will. It also seems that he is no longer under the influence of the hallucinogenic "plasmids", with Norman stating that he has been undergoing a "transitioning stage" during his last confrontation with Peter; furthermore, his speech is more coherent in his Goblin form, suggesting that he is no longer hallucinating as a result of the Oz formula. They kidnap Spider-Man, tie him to a chair, and force him to join them. The Goblin considers Parker to be his 'true' son and believes Parker belongs with him. In a battle between the Ultimate Six and the Ultimates at the White House, Harry is used as a trump card by Nick Fury. Harry pleads with his father to stop. Norman is about to change back when a trigger-happy Iron Man blasts him from behind, severely altering Norman's genes and causing him to lash out at the S.H.I.E.L.D. personnel before being shot down to Harry's horror. He is again taken into custody. At the end of the issue, he is revealed to be in cryogenic suspension, with half of his face in Goblin form on account of Iron Man's reckless shooting.

In the Ultimate Spider-Man video game, the Beetle, a Latverian mercenary, breaks him out to provide samples for Latverian experiments in creating super-soldiers. The Goblin rampages around New York City, but is stopped by Spider-Man after a confrontation in the UN Conference Building.

In Ultimate Spider-Man #112, Norman Osborn is again in semblance of a human, and is kept in a high-security cell with other superhuman prisoners. When contacted by Carol Danvers, Norman states that he will answer only to Fury; he then transforms into the Goblin, and breaks away from security measures, the OZ in his system having re-worked his body in a further process of what he refers to as 'Evolution'. In #113, the reader is given a look into his state of mind. Though no longer haunted by 'Plasmids', the Goblin has given in to severe paranoia, believing everyone save him to be insane, and Nick Fury a tyrant, imprisoning anyone with the power to stand up to him.

In his breakout, he enlists the promised help of Electro as payback for freeing him; other Supervillains that escape include Omega Red, Kraven the Hunter, and what appears to be Gwen Stacy, the new Carnage. The Goblin's stratagem upon escape is simple; he resumes as Norman, then appears on a talk show, claiming that Nick Fury held him in a prison against his will, just as he was on the brink of creating a drug to solve America's military problems.

In issue #117, the Goblin goes into an explosive rage when confronted with a TV broadcast of a (staged) S.H.I.E.L.D. press conference with Harry declaring that Norman was evil and killed Harry's mother (the press conference in fact was held aboard the S.H.I.E.L.D. helicarrier and only transmitted to the TV Norman was watching), and ended up assaulting the helicarrier; Harry manifests a form similar to Norman's, but loses the resultant melee and is beaten to death when he returns back to his human form. With both the S.H.I.E.L.D. troops and Norman horrified at what he's done, he reverts to his own human form, turns around and asks to be killed -- Carol Danvers, in charge of S.H.I.E.L.D. while Nick Fury is away, simply says "Gladly," before obliging.

Since Norman Osborn's powers derive from the OZ formula, his strength derives from how much he is exposed to. When the Green Goblin is created, the smaller dosage gives him green claws, horns and head, though the rest of him is human like in appearance. When he returns, he uses larger dosages of OZ to become larger and completeley green, with more crests. When Osborn overdoses on OZ, his horns, stature and muscles become larger, as does the number of crests. Osborn later develops a way to transform without OZ into a larger, more powerful form, making injections obsolete.