At the game's beginning Bruce Banner is hiding in a forest cabin within the American Badlands. In this self-imposed isolation he has been experimenting with creating a device that will help him cure his condition. Bruce chose this remote locale so that he does not have to worry about transforming into the Hulk and endangering the lives of innocents. Even in this peaceful secluded place he still finds frustration because Banner is not making much progress towards a cure.
Bruce is contacted through his laptop by his friend and psychiatrist Doc Samson. The doctor warns Bruce that he should leave his exile and come and join him in a safe place. Not only is Samson worried about his friends mental health but he is also worried about the military capturing Banner again. He tells Banner that a shadowy figure, Emil Blonsky, has requisitioned an entire military division in a nearby city and that they are on the hunt for him. Banner appreciates his friend's compassion but insists that no one knows of his whereabouts.
However, the military has already located his secret cabin. Emil Blonsky studies the cabin from a distance through binoculars as he discusses his next move with General Ross. The military division is officially under General Ross' command. Their orders and assignment are solely to hunt down and neutralize the Hulk by any means necessary. But at the beginning of this game it seems that General Ross is being manipulated by the mysterious Emil Blonsky. Blonsky is the Special Director of “The Division” - a secret government agency that studies and eradicates mutant threats.
Under Blonsky's orders, a fire team approaches Bruce Banner's cabin fires upon the west wall with a shoulder-mounted rocket launcher. The rocket completely levels the small wooden cabin and the Hulk immediately rises from the rubble seething with anger. The Hulk fights his way past the small military division by destroying tanks, helicopters...anything that gets in his way. Eventually the Hulk escapes completely by leaping out of the canyon.
Emil Blonsky and General Ross survey the ruins of Banner's cabin. The General berates Blonsky for letting the Hulk get away but Blonsky does not seem to care. He seems more interested in what Bruce Banner left behind in his cabin. Emil Blonsky notices a bio-container buried in the burning rubble. In order to save it from destruction, Blonsky reaches into the flames and grabs it himself. Immediately he is bathed in a green sphere of gamma waves.
A half-naked Bruce Banner stumbles upon the church where Doc Samson has promised to keep him safe. Samson tells him that they can resume Bruce's research that he has a plan, a way for them to control the Hulk. Doc Samson hands Bruce a visor which can “perform read or write operations directly into a patient's mind”. When Banner wears the device Doc Samson is able to force feed mission objectives into his mind that are dormant until Banner is transformed into the Hulk. “Think of it as a video game,” Samson says.
Meanwhile, Ross and Blonsky got into an argument about the mysterious prisoner, Mission Directive, secure in the Vault. The former warns the latter that he will get him if he finds out who or what is Mission Directive. After the argument, Blonsky sees a creature in the mirror, reflecting of what he will become after being exposed by the gamma waves earlier.
Just then, Hulk gets into an encounter with a creature who blames him for turning him into an Abomination. Because of his transformation is not stable, he gets beaten up. In the morning, Blonsky, half-naked, blames his own destruction to the Hulk.
Samson sends the Hulk into the Badlands to get some equipment from the Hulkbusters. Afterwards, Hulk gets into an encounter with a Hulkbuster prototype and defeats it.
Meanwhile, Blonsky is talking with his bodyguard, Mercy, about Ross. He refuses to tell her about his mutation and sends her to find Banner.
The Hulk goes to a nuclear plant to find the nuclear rods. However, Mercy fights him with her telekinesis and teleportation powers. After being defeated, she reveal that Blonsky is following her movements with a tracking device and is about to tell Hulk about Mission Directive. However, she is killed in an explosion. Banner, after escaping, encounters an evil personality in his mind, Devil Hulk.
The Hulk destroys buildings and kills innocent people because he is under an illusion of Samson ordering him to destroy Division buildings. This brings trouble as Samson reveals that he is working for Ross because he fears for the Hulk going out of control. Ross fights him with a gigantic Hulkbuster mech. He is defeated and Samson orders him to let him deal with Hulk. He puts the latter into hypnotic sleep.
Banner is shown taken to the Vault where Blonsky tries to find out how to control gamma mutations. This leads him to realize that Blonsky is the Abomination. While being chases, he transforms, finally revealing his identity. The two escape from the Vault.
Outside the church, Banner is angered that Samson has betrayed him. However, the latter has managed to have gotten a component for the machine. However, in order to do that, he uses Banner's captivity as a diversion. Banner forgives Samson and continues looking for components of his machine.
However, after finding the components, Ross finds their hideout and tries to attack but fails. Inside, Samson activates the machine that allows Banner to go into his mind.
Inside, the Devil Hulk fights Hulk, but loses. He claims that he is just a child, but Hulk punches. Devil Hulk pleaded to Hulk and disappears, bringing peace into Banner's mind.
Meanwhile, Blonsky is shown in a cave where he talks to the Abomination that he doesn't want power, only his life back. He transforms and leaves the cave.
Banner and Blonsky go to the Vault where the former reveals of Mission Directive. It was his wife, Nadia, who is diagnosed with ovarian cancer at early pregnancy. Because of this, Blonsky exposes her with gamma radiation to cure her. Instead, she is transformed into an aquatic mutant and this is the reason why Blonsky is obsessed with search for taking control of gamma transformations.
Banner tells Blonsky to put all this to an end. However, because his wife and unborn child are now dead, the latter blames the former for his troubles. He transforms into the Abomination and is about to "return the favor a thousand times over".
The chase leads Hulk and the Abomination to the dam where the latter plans to kill everyone by destroying the dam.
After being defeated, the Abomination gloats to Hulk that he didn't win and smashes the dam. He presumable drowns as he whispers the name of his wife, Nadia. The Hulk uses the rocks to stop the water from going into the city.
However, despite the heroic act, Ross still blames the Hulk for destroying the dam. Banner and Samson are watching helicopters search for the former. When Samson says that he can persuade some people to help Banner, the latter says that people don't trust him because he's the Hulk and he can't force people to understand that fact. Just then, a helicopter comes and a soldier tells Banner to give up.
Instead, Banner transforms into the Hulk and goes to the Badlands.