The game begins with Dr. Doom and the Masters of Evil launching an attack on the S.H.I.E.L.D. Helicarrier U.N.N. Alpha. Nick Fury sends out a distress call to all available super heroes for assistance. Captain America, Thor, Spider-Man and Wolverine respond to the call. Along with the other heroes, they save the Helicarrier from the forces led by Scorpion, Bullseye, Winter Soldier, Radioactive Man, and Fin Fang Foom. In the wake of the attack, Nick Fury is given permission to start a task force to confront the Masters of Evil and Iron Man allows them to use Stark Tower as their headquarters. Fury asks the heroes to investigate an odd message received from Dum DumDugan on the Omega Base, a S.H.I.E.L.D. mobile research facility. The team defeats
super villains M.O.D.O.K., Crimson Dynamo, and Mysterio to prevent the Omega Base from crashing in to a dam and launching several gamma bombs. With their mission successful, the heroes travel to Atlantis, where the inhabitants are being mind-controlled by Attuma, who has usurped Namor from his throne. With the help of nano-technology that enables them to breathe and move freely underwater, the heroes are able to save Namor and defeat Attuma and Tiger Shark. After defeating Attuma, the heroes encounter Mandarin, who unleashes the Kraken, which the team defeats by toppling pillars on it.
They then travel to the Valley of Spirits to confront Mandarin in his palace. After his defeat, he reveals that he attempted to take command of the Masters of Evil and, upon failing, left the group. He suggests that the Mandarin they saw in the catacombs was actually Loki, god of mischief. Upon returning to base, the team learns that Nightcrawler and Jean Grey have been kidnapped. Due to the involvement of mystical forces, Nick Fury has the team relocated to the Sanctum Sanctorum. Professor X tracks Nightcrawler to Castle Doom, but upon trying to transport the heroes there they are sent to Murderworld by a spell from Baron Mordo. After defeating a mind-controlled Jean Grey, Rhino, and Shocker, the heroes battle a large mech, piloted by Arcade. Victorious, the heroes learn that Dr. Doom has used Nightcrawler to access Mephisto’s Realm, and the team is sent in pursuit.
Upon arriving, minions of Mephisto kidnap Jean Grey and Nightcrawler. Blackheart, Mephisto’s son, puts them in separate cages above the Infinity Vortex, stating one must be saved and the other sacrificed before the team can defeat Mephisto. During their battle with Mephisto the sacrificed hero returns, resurrected by Mephisto, but now under his control. As a final effort, the resurrected hero sacrifices their life to defeat Mephisto and allow the team to escape. Meanwhile in Asgard a massive army of Super Soldiers attacks and imprisons the Asgardian gods. The heroes travel to Valhalla to liberate it from its invading force and free Heimdall, Tyr, and Balder. Then they fight the Wrecking Crew to open Bifrost Bridge in order for reinforcements to arrive. Looking for Odin in Niffleheim following a fight with Kurse and Ulik, they find his shattered Twilight Sword and learn from Ymir that Doctor Doom and Loki have taken Odin to Raven’s Spire. After Loki is seemingly defeated at Raven’s Spire, the team frees the Destroyer Armor to use against Doctor Doom. Loki, disguised as Fury, reveals himself and his plot to have the heroes free the armor for nefarious purposes. As heroes defeat Loki and the armor, Doctor Doom appears and reveals that he has stolen Odin’s power. He uses it to attempt to eliminate the heroes, but Uatu the Watcher saves them and transports them to the Inhumans’ base on the moon.
Uatu reveals the only way to defeat Doom is to find the M’Kraan Crystal and steal the Muonic Inducer from Galactus (who is currently attacking the Skrull homeworld). The team is sent to the Shi’ar Empire where they fight Deathbird and the Imperial Guard in order to restore Lilandra Neramani to the throne and gain a portion of the M’Kraan Crystal. After retrieving the crystal, the heroes travel to the Skrull homeworld and with the help of the Silver Surfer, the heroes disable Galactus and steal the Muonic Inducer. Meanwhile Doctor Doom conquers Earth, corrupting and creating clones of many of the heroes. In a final effort, the team travels to Latveria to confront Dr. Doom. The heroes use the M’Kraan Crystal and Muonic Inducer to weaken Doom. As the heroes weaken Doom, he is blasted by a bolt of lightning sent by a rejuvenated Odin, leaving nothing but his mask behind. As the heroes meet on the repaired Helicarrier, Nick Fury informs the heroes that the team must disband and asks if S.H.I.E.L.D. can count on them when another threat happens. Captain America assures Nick that the world can count on them.” Meanwhile, Galactus vows revenge on the heroes who stole from him and plans to destroy Earth.