McCullen is revealed to be using the same nanotechnology to build an army of soldiers with the aid of the Doctor (Joseph Gordon-Levitt), planning on using 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 (Byung-Hun Lee) and the Baroness to retrieve the warheads with assistance from Zartan (Arnold Vosloo). After a fight, Storm Shadow and the Baroness retrieve the warheads and take them to Baron DeCobray, the Baroness's husband, for him to weaponize. Making their way to Paris, the Joes pursue the Baroness and Storm Shadow but are unsuccessful in stopping them from launching the missile. The nanomites destroy the Eiffel Tower and some of the surrounding area before Duke manages to hit the kill switch, but in doing so is captured and taken to McCullen's base under the Arctic.The Joes locate the secret base and fly there as McCullen loads three missiles with nano-mite warheads. After Snake Eyes takes out one, Ripcord pursues the remaining missiles in a stolen M.A.R.S. prototype Night Raven jet while Scarlett, Breaker, and Snake Eyes infiltrate the base. Snake Eyes duels and prevails over Storm Shadow. Duke learns that the Doctor is Rex Lewis, Ana's brother believed to have been killed by a mistimed airstrike during a mission led by Duke - also the origin of the alienation between Duke & Ana. Rex had encountered Doctor Mindbender (Kevin O'Connor) in the bunker and was seduced by the nanomite technology, taking too long to retrieve the data and getting caught in the bombing which disfigured him. After freeing Duke, the Baroness gets subdued as the Doctor reveals he has implanted her with nanomites which has put her under his control for the past four years. Attempting to kill Duke, McCullen ends up being burned, so he and the Doctor flee to an escape vessel. Duke and the Baroness pursue him while the Joes fall back when the Doctor activates the base's self destruct sequence.
The Doctor assumes the identity of the Commander, having healed McCullen's burned face with nanomites, encasing it in silver and naming him "Destro", which places McCullen under the Commander's control. They are captured by G.I. Joe soon after. On the supercarrier USS Flagg, the Baroness is placed in protective custody until they can remove the nanomites from her body. Meanwhile, Zartan, having had his physical appearance altered by nanomites, infiltrates the White House during the missile crisis and assumes the identity of the President of the United States of America (Jonathan Pryce).