The four voice actors providing the voices to the 4 different Spider-Men in this game have each previously provided voices for a Spider-Man TV series over the years: Neil Patrick Harris who voices Amazing Spider-Man voiced Spidey in Spider-Man (2003). Josh Keaton who voices Ultimate Spider-Man voiced Spidey in The Spectacular Spider-Man (2008). Dan Gilvezan who voices Spider-Man 2099 voiced Spidey in Spider-Man and His Amazing Friends (1981). Christopher Daniel Barnes who voices Noir Spider-Man voiced Spidey in Spider-Man: The Animated Series (1994).
Features 3 actors who have voiced the character "Deadpool" in previous games and TV series: X-Men Origins: Wolverine (2009), John Kassir for Marvel: Ultimate Alliance (2006) and Nolan North for Hulk Vs. (2009). However, in this game Nolan North gets voice acting duties for Ultimate Deadpool and John Kassir plays one of Deadpool's fan boys.
One of the writers of the game, Mark Hoffmeier also worked on the well-received Spider-Man: The Animated Series (1994) on Fox Kids before working on the game. Some concept from the animated series influenced the game, including Madame Web enlisting multiple versions of Spider-Man (as seen in the series' two-part finale; Spider Wars, Chapter 1: I Really, Really Hate Clones (1998) and Spider Wars, Chapter 2: Farewell Spider-Man (1998)) and the concept of the Tablet of Order and Chaos. Another version of this, the Tablet of Time, appears in the animated series (as seen in Neogenic Nightmare Chapter 11: Tablet of Time (1996) and Neogenic Nightmare Chapter 12: Ravages of Time (1996)). The game is also notable for inspiring the 2014 Spider-Verse comic event which was penned by Dan Slott, who also created the story basis for the game. Ironically enough, the Spider-Verse comic inspired the Oscar winning film Spider-Man: Into the Spider-Verse (2018) and inspired concepts in the fan favorite film, Spider-Man: No Way Home (2021).
In a cutscene during the Electro level, Electro refers to Ultimate Spider-Man (voiced by Josh Keaton) as "The Spectacular Spider Schmuck". This is a possible reference to the animated series, The Spectacular Spider-Man (2008), which also features Keaton in the role of Spider-Man.
The voice actor of Ultimate Electro, Tom Wilson, also played Biff Tennen (and the members of the Tannen family) in the Back to the Future Trilogy; Back to the Future (1985), Back to the Future Part II (1989), and Back to the Future Part III (1990), which also one of the most famous stories featuring time travel.