It started in the past where James McCullen ancestors who sells weapons to both side to gain his fortune. In the near future, weapons expert James McCullen has created a nanotechnology. A weapon capable of destroying an entire city. His company MARS sells four warheads to NATO. Duke and Ripcord represent the US Army to deliver the warheads but was ambushed by the Baroness who happens to be Duke ex-fiancee. The Cobras show their weapon technology in order to retrieve the warheads. The US army weapons were no match to the Cobras. Duke and Ripcord try to protect the warheads but were no match. They were rescued by Scarlett, Snake Eyes (Ray Park, and you know who he is) and Heavy Duty. They take the warheads to The Pit, G.I. Joe's command center in North Africa, and upon arriving. The head of the G.I. Joe team, General Hawk takes command of the warheads and excuses Duke and Ripcord, only to be convinced to let them join his group when Duke reveals that Baroness was his ex-fiancee.
McCullen is revealed to be using the same nanotechnology to build an army of soldiers with the aid of the Doctor. The Doctor plans to use the warheads to cause panic and bring about a new world order. Using a tracking device, McCullen locates the G.I. Joe base and sends Storm Shadow and the Baroness to retrieve the warheads with assistance from Zartan. GI Joes try to save the warheads but failed and was taken back by the Cobras. The warheads was taken back to Baron DeCobray, the Baroness's husband, for him to weaponize, and use them to destroy the Eiffel Tower to serve as a show of the warhead's destructive power. The GI Joes managed to follow the Cobras at Paris and try to stop then but are unsuccessful in stopping them from launching the missile. Duke manages to hit the kill switch and thus save Paris, but in doing so he is captured and taken to McCullen's base under the Arctic. The G.I. Joes managed to locate the secret base where McCullen loads three missiles with nano-mite warheads but was too late as McCullen already lauched the 3 warheads. Snake Eyes managed to stop 1 of the 3 warheads. Scarlett and Snake Eyes attempt to shut down the Arctic base, with Heavy Duty leading an attack on Cobra's forces, Duke learns that the Doctor is Rex Lewis, Ana's brother believed to have been killed on a mission led by Duke four years ago. During that mission, Rex was disfigured in the blast which everyone presumed had killed him. The Baroness resists the programming that was put into her four years ago by Rex and try to save Duke. Attempting to kill Duke, McCullen ends up being facially burned. He and Rex managed to escape. Duke and the Baroness pursue him while the GI Joes fall back when Rex activated the base's self destruct sequence.
Rex then heals McCullen's burned face with nano-mites, encasing it in silver as he christens McCullen "Destro" and assumes the identity of Cobra Commander before they are captured by G.I. Joe later. Baroness is placed in protective custody until they can remove the nano-mites from her body. Meanwhile, Zartan, having been earlier operated on by Rex, infiltrates the White House during the missile crisis and assumes the identity of the President of the United States.