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In the near future, weapons expert James McCullen has created a nano-technology capable of destroying an entire city. He had sold four war-heads to NATO, and the US Army is tasked with delivering the war-heads. Duke (Channing Tatum) and Ripcord (Marlon Wayans) are delivering the war-heads when they are ambushed by The Baroness (Sienna Miller) and Storm Shadow (Lee Byung-hun). Duke and Ripcord are rescued by Scarlett (Rachel Nichols), (Snake Eyes (Ray Park) and Heavy Duty (Adewale Akinnuoye-Agbaje). They take the war-heads to General Hawk (Dennis Quaid) head of the G.I. Joe Team.

Duke takes command of the war-heads and excuses Duke and Ripcord, but when Duke reveals that he knows the Baroness Hawk allows then to train to join GI Joe.

McCullen and his associate the Doctor (Joseph Gordon-Levitt) are revealed to be using the same nano-technology to build an army of soldiers. McCullen plans on using the war-heads to bring panic. Using a tracking device McCullen locates the GI Joe base and sends Storm Shadow and the Baroness to retrieve the war-heads. After a fight Storm Shadow and The Baroness retrieve the war-heads and take them to Baron DeCobray, the Baroness's husband for him to weaponize. They then plan to attack the Effiel Tower.

GI Joe track down the Baroness and Storm Shadow and pursue them through the streets of Paris but are unsuccessful in stopping them from launching the missile, the nano-mites eat through part of the tower before Duke hits the kill switch, but in doing so he is captured and taken to McCullen's base under the Arctic.

GI Joe locate the secret base and fly to the Arctic, meanwhile McCullen loads three missiles with nano-mite war-heads. Ripcord pursues the missiles while Scarlett and Snake Eyes rescue Duke.

The Doctor reveals he is Rex Lewis, the Baroness's brother that Duke left for dead on a mission four years ago. He was trapped in a bunker with Dr Mindbender (Kevin O'Connor) and learn about the nano-technology. He was disfigured in a blast which Duke and the Baroness believed killed him. The Baroness tries to free Duke but the Doctor reveals he has implanted her with nano-mites.

McCullen tries to kill Duke but he is unsuccessful and his face is burned as he flees with the Doctor to an escape vessel. Duke and the Baroness pursue him while Scarlett, Heavy Duty and Snake Eyes attempt to stop the missiles and shut down the Arctic base.

Ripcord destroys the first missiles before he takes off in a prototype jet, then he destroys the second before it reaches Moscow, in destroying the third war-head he has to take it to the atmosphere, he ejects and lands in Washington DC.

The Doctor heals McCullen's burn face, but in doing so he encases it in silver, and he declares McCullen to now be Destro, he then says that he is now the Cobra Commander. They are soon captured by GI Joe. In the White House the President (Jonathan Pryce) is killed and the master of disguise Zartan (Arnold Vosloo), who was surgically changed by the Doctor, takes his place.