Life for former United Nations investigator Gerry Lane and his family seems content. Suddenly, the world is plagued by a mysterious infection turning whole human populations into rampaging mindless zombies. After barely escaping the chaos, Lane is persuaded to go on a mission to investigate this disease. What follows is a perilous trek around the world where Lane must brave horrific dangers and long odds to find answers before human civilization falls.

When human forces discover the existence of the Vampire and Lycan clans, a war to eradicate both species commences. The vampire warrior Selene leads the battle against humankind.

Grief-stricken mother Christine Collins (Angelina Jolie) takes on the L.A.P.D. to her own detriment when it tries to pass off an obvious impostor as her missing child.