In 1983, the world is introduced to the first and most powerful mutant, En Sabah Nur, also known as Apocalypse, who awakens after thousands of years and is disillusioned with the world he finds. Determined to cleanse mankind and create a new world order with himself as its ruler, he recruits four followers, or "Horsemen," beginning with Cairo pickpocket Ororo Munroe, who can control weather. To complete his cadre, he enhances the powers of mutants, including magnifying the rage and grief of Erik Lehnsherr, harboring immense pain from personal loss.

Charles Xavier continues to lead his School for Gifted Youngsters and foster a haven for mutants. His old friend and now adversary, Magneto, has gone into hiding, attempting to live a normal life but is thrust back into the conflict after a personal tragedy. Mystique, independently working to rescue and safeguard mutants, finds young Nightcrawler and seeks to protect him from the growing conflict. With Apocalypse gaining power and assembling his Horsemen, including Psylocke, who can manifest weapons with her mind, and Angel, whose wings can carry him on lethal flights, the stage is set for a catastrophic confrontation. Xavier and his X-Men must confront an ancient mutant threat that endangers not just mutant kind, but the entire human race, as seen through the widening chasm between humans and mutants and the ominous threat to Xavier's dream of coexistence.