Left abandoned, starved to death as a baby in the harsh, unforgiving desert of ancient Egypt, ruled by Rama-Tut, a band of nomadic raiders found an infant, gray-skinned and freakish in appearance, abandoned by the settlers of Akkaba. The nomads took the child for their own, giving him the name En Sabah Nur, “The First One,” and teaching him to be "strong" in order to survive the desert as a child. This idea, that "the strong will survive," would shape Apocalypse's actions throughout time.
When En Sabah Nur was an adult, he was captured with his nomadic clan and forced into slave labor under the Grand Vizier Ozymandias. He quickly became a rebel and was even killed by agents of Ozymandias, only to be revived soon after due to his mutant powers. Believing himself "strong" and blessed, En Sabah Nur discovered Rama Tut’s technology underneath Egypt, and soon destroyed the Egyptian rulers around him and twisted Ozymandias into the being he is today.
Apparently, Apocalypse would use Rama Tut’s technology to "regenerate" for long periods of time, becoming more and more powerful when awakening. He was also known to have traveled around the world during these ancient years, appearing to various primitive cultures as their death god. At some point, when traveling through Mongolia, Apocalypse encountered a spaceship abandoned by the planet-judging aliens, the Celestials. His travels then became fueled by a single-minded purpose-- to find the key that would unlock the secrets to this alien technology. He found it in the person of Nathan Summers, then wandering various eras as the Traveler. The two fought, and although Apocalypse was nearly killed, he was saved by Ozymandias and taken to the Celestial ship. Apocalypse’s blood had become infected with Summers’ techno-organic virus during the battle, and the infection allowed Apocalypse to not only transform into an even more powerful being, but to also interface with the Celestial ship, claiming it as his own.
Another reawakening occurred during the 12th century Crusades. Apocalypse's regeneration chamber was thought to be a temple of great power, and was sought out by the Black Knight and his friend Bennet du Paris, whom Apocalypse recognized as a mutant, and created him into the being known as Exodus.
Later, Apocalypse surfaced in late 19th-century England, about the same time Darwin was proposing his "survival of the fittest" theories. Apocalypse, searching for underlings, met the scientist Nathaniel Essex, whose own desire for scientific knowledge led him to foresee the abundance of mutants that would occur in modern times. Apocalypse earned the allegiance of Essex, turning him into the being now known as Mister Sinister, but was soon defeated by the time-lost mutants, Cyclops and Phoenix.
In recent years, Apocalypse was somehow awakened by the arrival of Cyclops’ son from the future, Cable. Apocalypse made another move against Cyclops and his team, X-Factor, by pitting them against a team of his own creation, the Alliance of Evil. Although he never used his Alliance again, Apocalypse soon formed the Horsemen of Apocalypse to plague humankind, when his ideas to "cull" humanity in order for the rise of mutant supremacy were beginning. He fought X-Factor again, and even captured their member Angel to turn into his Horseman of Death, although he defected, to be later replaced by X-Factor's ally, Caliban. Later, Apocalypse infected Cyclops' son, Nathan (who would become Cable) with the techno-organic virus (which would also inadvertently create Cable’s counterpart, Stryfe, as well as ensure his own infection when he met Cable as the Traveler) but was defeated by X-Factor in final battle.
Apocalypse abandoned his Horsemen in favor of his Riders of the Storm (a.k.a. the Dark Riders) and later became the target of time-traveling Stryfe, who, as a clone of Nathan, was raised by Apocalypse in a horrific alternate future in which Apocalypse had risen to power. Eventually, Stryfe left Apocalypse withered and dying on the surface of the moon, where he was confronted by his Dark Riders and left for dead.
Later, Apocalypse tried to revive his team of Horseman, transforming the Hulk into War, until Hulk broke free and went his own way. Over time, Apocalypse managed to re-create his Horsemen, transforming recognized heroes and villains into versions of War, Pestilence, Famine, and Death, (specifically Deathbird, Caliban, the X-Men’s associate, Rory Campbell, and Wolverine.)
About the same time, Apocalypse apparently encountered and agreed to lead a faction of the Skrulls, who were investigating their own race's mutations. Apocalypse led these Skrulls in finally assembling what Apocalypse called "the Twelve," mutants who Apocalypse would absorb powers from, giving him god-like abilities to re-create the world in Apocalypse's image. Many of the Twelve were members of the X-Men, and the team assembled to stop Apocalyspe. In the process of absorbing all of the Twelve’s powers into himself, Cyclops was merged with Apocalypse instead of Nate Grey, whom Apocalypse preferred. Unable to cope with the influx of power due to Cyclops' involvement, Apocalypse rejected the power, escaping and abandoning his mission, although Cyclops' body was seeming killed in the process.
Soon, Phoenix and Cable left the X-Men in order to focus their attention on a search for Summers, whom they believed to still be alive. They tracked Apocalypse to his birth place in Egypt, where Summers, now an amalgamation of himself and Apocalypse, fought them. Ultimately, Jean was able to physically rip Apocalypse from Summers' body using her mental powers, and Cable destroyed Apocalypse's essence with his own telepathic powers.
However, Apocalypse did not die, but managed to regenerate in a tomb in Akkaba. He immediately set about creating more Horsemen, this time recruiting Gazer, Sunfire, and Polaris. Gambit had also sought Apocalypse, hoping to be a mole for the X-Men but becoming twisted by Apocalypse instead. When Apocalypse’s power once again was at his peak, he confronted the X-Men at their mansion headquarters, which had since become a camp of refugees from the events of House of M|M-Day. Despite recruiting several refugees to his cause, Apocalypse was forced to retreat by the X-Men and the Avengers. Ultimately, it was revealed that Apocalypse had never been able to use the Celestials' technology without their notice, and Apocalypse believed that they would soon exact their retribution. Apocalypse sought death as an escape route, but the Celestials appeared, resurrecting him in order to spirit him away for their judgement.