Reed Richards (IOAN GRUFFUDD) is a bankrupt but brilliant scientist who, with friend Ben Grimm (MICHAEL CHIKLIS), approaches former schoolmate and current billionaire businessman Victor Von Doom (JULIAN MCMAHON) with a request. Hoping to study some approaching cosmic radiation that he believes may have sparked life on Earth in its only other pass by our planet, Reed not only asks for financial aid, but he also requests the use of Doom's space station. Always wanting to see Reed fail in a spectacular fashion, Victor agrees.
Joining them is Victor's director of genetic research and current girlfriend Sue Storm (JESSICA ALBA) who once had a relationship with Reed, as well as her adventurous and brash playboy brother Johnny (CHRIS EVANS) who will pilot their mission. Unbeknownst to them, however, the cosmic storm is arriving sooner than Reed calculated, exposing the entire crew to high doses of radiation that fundamentally alters their DNA.
Back on Earth, they soon learn exactly how. Reed suddenly has the ability to stretch, bend and flatten his body like rubber, while Sue can turn invisible and create powerful force-fields around her or others. Johnny can cause any part of his body to catch on fire without any harm to him, while Ben has been turned into a monstrous figure who appears to be comprised entirely of rock. As he's the only one who can't will his super power into action, his new appearance causes his wife to leave him, but he's later consoled by a kind blind woman, Alicia Masters (KERRY WASHINGTON), who doesn't care how he looks.
As Reed tries to come up with a solution for their new abilities, the opportunistic Johnny seizes the moment to grab the limelight. After they end up preventing a catastrophe on a bridge high above the river, the press deems them the Fantastic Four and Johnny revels in the publicity. Yet, little do they realize that Doom was also affected and can now control electricity, a power that's slowly turning his skin into some sort of organic metal. With Reed racing to recreate the space storm with hopes that he can revert himself and his friends, the group must deal with the megalomaniacal Doom who's progressively becoming more dangerous and sees the group as the only thing between him and world domination.