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In a near future, various dimensions start collapsing. Thor, Black Bolt, and Black Panther are investigating the collapse before encountering a dead Captain America and versions of themselves, who they duel and defeat. In the future, a dying Nick Fury sends his robotic aid, Jocasta, to the player, with a message telling the player to get a group of heroes to restore the balance. After obtaining the heroes Captain America, Black Widow, and Iron Man, Ultron attacks Stark Tower. While fighting off the Ultrons, Jocasta remarks that something seems "off" about them, and the heroes see strange things, like a War Machine armor Tony Stark didn't make, and a hostile Vision.

Eventually, the Ultrons leave without much visible damage, but Jocasta finds out that they kidnapped a Stark Industries employee, Jemma Simmons, who was studying alternate dimensions. The heroes rescue Jemma from AIM. Jemma tells them that they took her research in dimensions. Soon afterward, while trying to locate MODOK, the heroes encounter dimensional alternates of several heroes and villains, and realize that AIM has built a device to send people between dimensions.

Eventually, the heroes take down MODOK, who reveals that he was trying to research Ultron by summoning his dimensional alternates before Red Skull stole the dimension transporter. After that, SHIELD agents begin to be attacked on the streets by thugs with ISO-8 enhanced weapons, and supposedly secret S.H.I.E.L.D. bases are raided. After fighting off the thugs as well as the Hand, the team chases after Red Skull and Hydra.

After defeating Red Skull and Ultron, a large dimension transference device is opened and dimensions begin to collapse. Future versions of the heroes appear, attempting to destroy this world to save their own. Agent Carter reveals to the team that Captain America was imprisoned after he refused to help destroy the world. Eventually, the team defeats all of their future selves and save the world by splitting dimensions through Jocasta, with help from MODOK.

Afterwards, Jemma Simmons is contacted by her Marvel's Agents of Shield version, who informs her that their dimension's Helicarrier is under attack from the Inhumans, led by Raina. A team of Daisy Johnson, Agent Coulson, and Melinda May, with support from the arriving Sif, manage to defeat the Inhumans and clear them out of the Helicarrier. However, Gordon, a teleporting Inhuman, teleports Raina and himself to Afterlife, an Inhuman town. Agent Coulson's team infiltrates Afterlife, where, after defeating several waves of Inhumans, they encounter Lincoln Campbell, a misguided Inhuman with the ability to control electricity.