Tom Holland was not allowed to read the script for this movie, since he revealed too many secrets for Spider-Man: Homecoming (2017). In one of the promotional videos for the movie, several of its cast members are in an interrogation room refusing to reveal any spoilers, and Holland's mouth is conspicuously taped shut.
Mark Ruffalo revealed that he was given a fake script due to his habit of accidentally spoiling past Marvel movies. He jokingly claimed in an interview that the fake script was better than the real one.
Doctor Strange has been studying for a few years since his solo movie, and is now considered one of the more powerful characters in the Marvel Cinematic Universe. The writers also wanted to have him come off as sort of "the adult in the room" throughout the movie.
(at around 1h 20 mins) Drax's line "I'll do you one better: Why is Gamora?" was ad-libbed by Dave Bautista. In an interview, Dave says that Chris Pratt actually gave him the idea for the line.
Tom Holland said that although he is a big fan of Chris Pratt and loved working with him, their scenes together were often challenging. Pratt's tendency to joke in and out of character made it hard for Holland to keep a straight face at times.
Kenneth Branagh: The director of Thor (2011) can be heard at the beginning of the movie issuing the distress transmission that the Asgardian ship was being attacked.
Stephen McFeely: (at around 54 mins) The film's screenwriter makes a cameo alongside William Hurt during his conference call.