The character of Jessica Jones was originally supposed to be in the animated series, but she was replaced by Nico Minoru from Runaways.
Originally titled Spider-Man: Freshman Year.
The show was first intended to be set in the Marvel Cinematic Universe (MCU), and tell the origin of that Spider-Man (played by Tom Holland in the movies). It was later decided to be set in an alternate universe, with the show being described as "an extended What If episode."
The intro and outro have several visual homages to original Spider-Man artist Steve Ditko's work. An example is the head shots of all the major characters in a spiderweb.
Hudson Thames previously voiced Peter Parker/Spider-Man in What If...? (2021): What If... Zombies?! (2021). That particular variant was from the Earth-89521 version of the Marvel Universe.