Coming from a long line of arms dealers, MARS Industries CEO James McCullen (CHRISTOPHER ECCLESTON) has arranged to sell a number of warheads to NATO, but these aren't the normal military garden variety. Instead, they contain nanotechnology -- created by his own mad scientist, Rex Lewis (JOSEPH GORDON-LEVITT) -- that once activated, will quickly eat through anything they come into contact with, be that military equipment or even entire cities.
Due to their volatility, they obviously need a military escort and get that from a team of U.S. Army rangers led by Duke (CHANNING TATUM) and Ripcord (MARLON WAYANS). Little do any of them know, however, that they're going to be attacked by forces working directly for McCullen, or that the likes of Ana DeCobray (SIENNA MILLER), ninja Storm Shadow (BYUNG-HUN LEE) and Zartan (ARNOLD VOSLOO) will outmatch them due to technologically advanced weaponry and a similarly equipped flying craft.
In fact, they probably would have lost the case of those four nanotechnology warheads to Ana's team if not for the rescue efforts of General Hawk (DENNIS QUAID) who's sent his G.I. Joe forces to fend off the villains. They're the best of the best of the various military forces, and it's not long before Duke and Ripcord are inducted into that elite force.
With the U.S. President (JONATHAN PRYCE) hoping they succeed, they take their place alongside other members of the team including the alluring but tough Scarlett (RACHEL NICHOLS), ninja Snake Eyes (RAY PARK) and technology expert Breaker (SAID TAGHMAOUI).
When McCullen's goons get their hands on the four warheads, it's up to Duke and the rest of the G.I. Joe specialist to prevent them from being deployed upon the world, a quest complicated by the fact that Duke and Ana once were romantically involved.