The story of follows the mutant villain Apocalypse , who has opened a rift between the Marvel and Street Fighter universes to pull fighters into his own realm . Believing in "survival of the fittest," he seeks to destroy the weak and force humanity to evolve into a stronger species, considering himself the pinnacle of human evolution. Key narrative elements include:

In a new plot twist, Apocalypse captures Akuma and uses advanced technology to transform him into Cyber-Akuma (Mech-Gouki in Japan)—a mechanized, super-powered horseman designated as "Death".

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Heroes from both worlds must join forces to stop Apocalypse from annihilating humanity and ruling both universes.

Each character has a unique ending upon defeating the final boss, Cyber-Akuma. For example, Captain America returns to his own time, while Ryu continues his search for a worthy opponent.

Shadaloo leader M. Bison also exploits the chaos. Using Apocalypse's technology, he transforms Charlie Nash into the mind-controlled super-soldier Shadow .