Hudson Thames voices Peter Parker / Spider-Man, reprising his role from the Marvel Studios animated series What If...?

(2021–2024), with Kari Wahlgren, Grace Song, Eugene Byrd, Zeno Robinson, Colman Domingo, Hugh Dancy, and Charlie Cox also starring.

It was originally intended to be set in the main MCU continuity but the creative team found this too restrictive and decided to move it to an alternate timeline, allowing the series to explore familiar ideas and characters in new ways.

[38][independent source needed] Marvel Studios' Feige, Louis D'Esposito, Winderbaum, and Dana Vasquez-Eberhardt were executive producers alongside Trammell.

[42] The series depicts the origin story of Peter Parker / Spider-Man, which was never explored in detail in the Marvel Cinematic Universe (MCU) films;[3] Feige stated in 2015 that they decided to not retell the character's origin in Captain America: Civil War (2016),[43] which was the character's first MCU appearance,[3] since there had already been two versions depicted in the Spider-Man films directed by Sam Raimi (2002–2007) and Marc Webb (2012–2014) and the studio decided to "take it for granted that people know that".

[43] The series was originally planned to be set within the MCU's "Sacred Timeline" before the events of Civil War, but the creative team found this to be too restrictive regarding which characters and comic book elements could be included.

[29][46][47] Winderbaum said the series was "so essentially Spider-Man" because it features Peter trying to juggle high school, caring for his aunt May, and being a superhero.

[41] Charlie Cox was revealed to be reprising his role as Matt Murdock / Daredevil from previous MCU media in July 2022,[39] while Paul F. Tompkins was cast as Bentley Wittman.

[52] In September 2023, a United States Copyright Office filing for the series revealed that Hudson Thames was voicing Peter Parker / Spider-Man, reprising his role from the first season of What If...?

(2021),[4][53] with Eugene Byrd as Lonnie Lincoln, Grace Song as Nico Minoru, Hugh Dancy as Otto Octavius, Kari Wahlgren as May Parker, and Zeno Robinson as Harry Osborn.

[4] The creative team were struggling to settle on an actor they felt could live up to Norman Osborn's reputation when Zwyer suggested casting Colman Domingo.

[11] In December 2024, Vincent D'Onofrio was revealed to be reprising his role as Wilson Fisk / Kingpin from previous MCU media,[28] with Cathy Ang as the voice of Pearl Pangan.

[15] Ahead of the series' premiere in January 2025, more actors were revealed to have been cast in the series: Robin Atkin Downes as Dr. Stephen Strange; Anjali Kunapaneni as Jeanne Foucault; Erica Luttrell as Asha; Aleks Le as Amadeus Cho; Zehra Fazal as Carla Connors; Jake Green as Butane; Mick Wingert as Tony Stark / Iron Man, reprising his role from What If...?

; Roger Craig Smith as James Sanders / Speed Demon and Dmitri Smerdyakov / Chameleon; Anairis Quiñones as Maria Vasquez and Carmilla Black; Travis Willingham as Mikhail Sytsevich and Thaddeus Ross; Sarah Natochenny as Mila Masaryk / Unicorn; Leilani Barrett as Big Donovan; and Jonathan Medina as Mac Gargan / Scorpion.

[36] Leo Romero was the lead character designer, with comic book artists Chris Samnee, Paolo Rivera, and Ethan Young also working on the series.

[65] King and IGN's Adam Bankhurst both highlighted the trailer's combination of classic Spider-Man references—including the art style and theme song—with contemporary animation and imagery.

[65][66] Discussing the trailer for Gizmodo, Justin Carter said it was "well worth the wait" and felt the series would be appreciated by people who wanted the MCU's Spider-Man to have some "smaller adventures".

The site's critical consensus reads: "Embracing the wholesome aesthetics of the webslinger's original comic run while adding some fresh plot wrinkles, this family-friendly Spider-Man is a lovable incarnation of the Marvel superhero.