Boasting "Unstoppable Movement" means Hulk can run across walls and other vertical surfaces, climb any wall by digging his fingers into concrete, leap huge heights and distances all under the player's control. Hulk's combat abilities also reflect this increased power; cars and buses are simply smashed out of the way (or in some instances turned into makeshift gauntlets for combat use) while fully charged attacks will toss vehicles, enemies and unlucky pedestrians into the air. At his most powerful the Hulk can perform one of five different ultra-powerful Devastator attacks including the Critical Atomic Smash and the Critical Thunderclap. These attacks will clear enemies out for a multi-block radius, flatten entire buildings, and cause massive damage to enemies. The game includes the voice talent of Neal McDonough reprising his role of Bruce Banner which he first began in the 1996 Incredible Hulk animated series, Ron Perlman (Emil Blonsky/Abomination) and Richard Moll (Devil Hulk).
Suddenly, Banner's cabin is destroyed by a missile. The Division, a specialized branch of the NSA dealing with the threat of mutated humans, is attacking. The Division is jointly lead by the psychotic mutant-hater Emil Blonsky and the Hulk's old foe General Thunderbolt Ross. Banner transforms into the Hulk, easily bests his assailants, and escapes to Samson's hideout in a secluded church. As Ross berates Blonsky for allowing the Hulk to escape, Blonsky impulsively grabs a vial from the remains of Banner's cabin and is engulfed in gamma rays.
As the game progresses, Samson uses a special device to control the Hulk through post-hypnotic suggestion, and sends him on various errands into the city and the badlands, either to help construct the machine or to hinder the ever-growing presence of the Division. Time is running out, as a new, darker personality is slowly taking control of Banner's mind.
Meanwhile, Ross and Blonsky's mutual animosity towards each other grows into open hostility, due to Blonsky's increasing paranoid and irrational behavior, especially his overstepping his authority to secure a mysterious prisoner, "Mission Directive", in the secret military research facility known as the Vault. After an argument with Ross, Blonsky loses control and transforms into a massive reptilian-like creature. Having become what he hates - a mutant - Blonsky dubs himself the Abomination. The Abomination goes on a rampage until the Hulk arrives. Although the Abomination is the stronger of the two, his transformation is not fully stable, and the Hulk bests him in combat. When the battle is over, Blonsky transforms to his human form before his men can arrive and blames the Abomination's rampage on the Hulk.
When Hulk is sent to fetch fuel rods from a nuclear power plant to power the machine, he finds Blonsky's bodyguard Mercy waiting for him. The two battle, and when the Hulk emerges triumphant Mercy reveals that she had no choice but to follow orders, as Blonsky has placed a tracking device in her skull and is monitoring her every move. Mercy attempts to reveal to the Hulk the true identity of Mission Directive and why Blonsky is so obsessed with it, but before she can Blonsky orders an air strike on the area. Mercy is killed and while Banner escapes with his life, the stress of the situation takes its toll and his evil alter ego, the Devil Hulk, begins to emerge.
Under the Devil Hulk's influence, the Hulk destroys civilian buildings, killing many innocents, under the illusion that Samson is ordering him to destroy Division locations. When Samson sends Hulk on a mission to retrieve a package from Division headquarters, he is lured into an ambush, as it is revealed that Samson has been conspiring with Ross, fearing the threat of an out-of-control Hulk. Ross faces the Hulk in a gigantic Hulkbuster mech, which the Hulk destroys. Having no choice, Samson puts the Hulk to sleep with his hypnotic device.
Banner is taken to the Vault, where Blonsky prepares to peel open Banner's mind, as he has become obsessed with discovering the secret of controlling gamma-based transformations. The agony of his interrogation draws out the Devil Hulk's power once more, and the Hulk breaks free. When Blonsky is cornered by the Hulk, the stress causes him to become the Abomination again, and his identity is revealed in front of the entire Division. Blaming the Hulk for ruining his life, the Abomination flees the Vault, as does the Hulk.
Back at the church, Banner confronts Samson for betraying him, but forgives him when Samson reveals that he used Banner's captivity as a diversion to secure a vital component of the machine. Before the machine can be completed, however, Ross discovers the church and orders it destroyed. The Hulk defends the church as Samson makes the final adjustments. Now Banner journeys into his own tortured psyche to defeat his inner demon. The Devil Hulk mocks the Hulk, calling him a weak child, but the Hulk stands his ground, besting the Devil Hulk in combat and banishing him from Banner's mind.
Emil Blonsky is not so fortunate. An outcast from society robbed of his dignity and position, he pleads with the Abomination for his life back. Instead, the Abomination appeals to Blonsky's obsession with Mission Directive, saying it will be the only way for him to get his revenge. He then mutates into a larger and much stronger version of the Abomination and heads for the badlands. The Abomination breaks back into the Vault, destroying all in his path. The Hulk follows, expecting a fight, and is surprised to find a heartbroken Blonsky cradling the dead body of a heavily mutated woman.
In tears, Blonsky reveals that Mission Directive was his pregnant wife, Nadia. Early in her pregnancy, Nadia was diagnosed with ovarian cancer, and Blonsky exposed her to gamma radiation in hopes of curing her. Instead, it transformed her into an aquatic mutant, and his reasons for obsessively pursuing the Hulk were in hopes of learning how to control the transformation and change her back. Banner tries to comfort Blonsky, but Blonsky, having lost everything he loved, blames Banner for his misery and transforms back into the highly mutated Abomination. Vowing to "return the favor a thousand times over", the Abomination heads for the local dam, as during his tenure with the Division Blonsky deduced that the destruction of the dam would destroy the city before it could be evacuated.
Both the Hulk and Ross' Division forces pursue the Abomination, and they have a final battle on top of the dam. After being beaten by the Hulk, the Abomination plays his final card. "You didn't win, Banner. Nobody wins when you're involved. When they print the morning edition, do you know what the headlines will say? No survivors." With a final whisper of "Nadia...", the Abomination smashes the dam apart, disappearing underneath the massive wall of water and presumably drowning. However, Blonsky is denied even a pyrrhic victory, as the Hulk creates a landslide to stop the flow of water, saving the city in the nick of time.
Despite this heroic act, Ross sees to it that the world blames the Hulk for the dam's destruction. Samson laments this turn of events, as he and Banner were nearly successful in curing Banner. Samson offers his help again, but Banner turns him down, as the world will never trust the Hulk, and he sets off on his own. The game ends as it begins, with the Hulk rampaging mindlessly across the badlands.