Following the gameplay style of past Lego titles, players are able to control 180 characters from the Marvel Universe, each with their own unique abilities. For example, Spider-Man can swing on his webs and use his spider-sense while the Hulk, who is larger than the standard minifigures, can throw large objects, as well as shrink down into Bruce Banner to access computers. Galactus was chosen as the main antagonist of the game. According to game director, Arthur Parsons, and producer, Phil Ring, one of the main settings of Lego Marvel Super Heroes is a Lego version of New York City. In addition, a Lego version of Asgard was created.
The creative team has also incorporated Marvel Comics co-creator Stan Lee in the game. He is a part of missions called "Stan Lee in Peril" (similar to "Citizen in Peril" missions from previous games). He is also a playable character and has several of the other characters' abilities (such as Spider-Man's webbing, a combination of the Human Torch's heat beam and Cyclops' optic blast, Mr. Fantastic's ability to grapple, Wolverine's adamantium skeleton when all health is depleted, and the ability to transform into a Hulk-like version of Lee).
Players can also explore the Marvel version of New York City, though they can only use a specific character and access buildings after the campaign is complete. Side missions are narrated by Deadpool and take place in buildings with their own storylines. There are a total of 15 missions in the main single-player campaign, followed by 11 side missions.
Many of the main LEGO minifigure characters are based on their appearance from the Marvel Cinematic Universe. Tony Stark is modeled on Robert Downey Jr., Nick Fury is modeled on Samuel L. Jackson, whilst Agent Phil Coulson is both modeled on and voiced by Clark Gregg, Captain America is modeled on Chris Evans, Black Widow is modeled on Scarlett Johansson, Bruce Banner is modeled on Mark Ruffalo, Clint Barton is modeled on Jeremy Renner, Loki is modeled on Tom Hiddleston, Thor is modeled on Chris Hemsworth, and Maria Hill is modeled on Cobie Smulders.