5 years ago, Bruce Banner, a military scientist, attempted to recreate the super soldier serum. Unfortunately, he is now on the run from the U.S. military, who want to capture the Hulk and use him as a weapon. At the moment, Bruce is living in Brazil, and communicating over the internet with someone known only as "Mr. Blue", in the hopes of a cure for his condition. When not looking for a cure, he works at a bottling plant.

Unfortunately for Bruce, some of his gamma-infected blood falls into a bottle at work one day, which kills the old man who ends up drinking the bottle. General "Thunderbolt" Ross deduces that Banner must be at the bottling plant, so he sends in a special team to get him, led by a Russian named Emil Blonsky. When the team finds Bruce, he ends up having to transform to the Hulk to escape. All of the soldiers except Blonsky are killed.

In order to get more research for Mr. Blue, Bruce has to return to his university in Virginia, where he first did his research. While he's there, he accidentally bumps into Betty Ross, who he was dating a few years ago. On the day that Bruce is ready to leave the university, he is attacked by the army once more, who want the Hulk. With them is Blonsky, who has taken an experimental super soldier serum and is now faster and stronger than before. Despite this, the Hulk still manages to stop him.

Betty and Bruce go on the run, and end up going to New York to meet Mr. Blue. Mr. Blue turns out to be a scientist named Samuel Sterns, who believes he has made a successful cure. They manage to get Bruce to transform to the Hulk, where the cure is tested and is successful. Sterns then reveals that he synthesized a sample of Bruce's blood that was sent to him, which he intends to use to help evolve mankind. Bruce is appalled by this and tries to convince him to destroy it, but the Army arrives and Bruce is captured.

When the Army leaves Sterns, Emil Blonsky bursts in and demands the gamma treatment that Sterns has made from Bruce's blood, as he wants the power of the Hulk. Sterns is reluctant at first, as the experimental super-soldier serum combined with the gamma treatment could mutate him in unexpected ways, but after Blonsky starts threatening him Sterns gives him the treatment. As Sterns predicted, the treatment mutates him, into something with the Hulk's strength but Blonsky's intelligence. As he leaves, Blonsky hits Sterns across the room, which makes some of the gamma treatment drip into Sterns' head.

Bruce convinces General Ross that he is the only person who can stop Blonsky, and is let out of the helicopter they are in. He falls to the ground and manages to transform to the Hulk just in time, as the cure wasn't completely perfect. The Hulk and Blonsky then battle, and the Hulk almost loses, before managing to get the upper hand. He then flees.

Thirty-one days later, Bruce is attempting to gain control of his transformations willingly. At the same time as he attempts this, General Ross is told by Tony Stark that a team is being put together.