Marvel's Spider-Man: Miles Morales is the second game in the PlayStation exclusive Marvel's Spider-Man series, following Marvel's Spider-Man (2018). It is centered around Miles Morales, a fictional comic book superhero who becomes Spider-Man as a Black teenager of Puerto Rican ancestry on his mother's side, following the death of Peter Parker. The game handles it differently compared to the original storyline in the comic books, continuing the narrative of the first game (and especially the DLC The City That Never Sleeps) where Miles Morales is bitten by a genetically-enhanced spider and gained powers similar to Peter Parker's. Miles trains under Parker and is still integrating in the role of a Spider-Man. In the game Parker does not die, but leaves to join his girlfriend Mary Jane Watson to cover a civil war, leaving Miles as the only webslinger in New York. The story focuses on the campaign of his mother Rio Morales, and the defense of his home neighborhood in Harlem and New York City against a high-tech criminal army called the Underground and Roxxon Energy Corporation who are in a gang war.

The game builds on the same type of gameplay as the original game, offering a large open world that can be explored at a fast pace by running on buildings and swinging with web shots. Most of the Manhatten map is still identical to the one of the original game, as the game is more of a smaller contained follow-up than a full-blown sequel. It now has a different theme however as it is set around Christmas time. Various types of quests and missions are offered with a mix of fights against groups of characters or relying on a more stealth based approach. Many are provided through an app citizen use to contact him. Stealth receives more attention in this title as Miles has the ability to become invisible for a short time. Other new abilities include bioelectricity where electricity is absorbed to use it as a weapon, for instance launching a Venom Punch, but also as a means to solve environment based puzzles.

As in the first game there are many collectibles (often providing bonuses and gadget upgrades) and side missions to earn activity tokens and experience points. Gradually more power are unlocked for Miles' new suits or for his visor. Some items also add to the story, for instance through time capsules that show portions of Miles early life and audio-focused collectibles that provide information about his family.