The audio log "The Thing Voicemail" has the Thing attempt to contact Reed Richards (Mister Fantastic), but the call goes straight to voicemail. The Thing expresses how he prefers having a neutral stance regarding the Superhuman Registration Act, feeling that the law is wrong, but also that he doesn't want to fight the government. The Thing becomes unavailable at end of the first act, eventually becoming playable again after completing the mission Guard Duty: Road Work. This voicemail serves as a reference to Fantastic Four Volume #3, Issue #539, which took place during the "Civil War" comic miniseries.

The opening sequence of the game set in Latveria starts as a loose adaptation of the 2004 Marvel Comics miniseries "Secret War". Daredevil, Luke Cage and Wolverine's designs from this story appear as alternate costumes.

One of the team bonuses "Former Horsemen" references when different heroes were Horsemen of the X-Men supervillain Apocalypse:

• Hulk debuted as War in the Incredible Hulk (1962) Issue #456.
• Wolverine debuted as Death in Wolverine Volume 2, Issue #145.
• Gambit debuted as Death in X-Men Volume 2, Issue #185. Gambit's design as Death appears in the game as an alternate costume.
• Iceman in the main 616 continuity has never been a Horseman of Apocalypse, but in the alternate "House of M" Earth-58163 timeline, Iceman is introduced as a Horseman in Black Panther Volume 4, Issue #7.

During the level Underground Politics, Deadpool can say a line while mimicking Titanium Man's Russian accent: "Hey, when we see Titanium Man, let's try to get him to say 'moose and squirrel!'" This is a reference to the Russian spies Boris and Natasha from the animated series "The Adventures of Rocky and Bullwinkle and Friends".

In the Prison level "Jail Break-in", a giant bar of soap can be found hidden in a prison cell, which can be used as a weapon. This is a reference to the commonly used prison saying, "don't drop the soap".