Jared Leto committed to capturing Michael Morbius' limping state and used crutches even off-camera. This proved to be troublesome for the crew, at times, when the actor reportedly took 45-minute treks to the bathroom. Pushing him in a wheelchair was a loophole solution around these delays.
The New York scenes were filmed in Manchester's Northern Quarter, United Kingdom. All city lights, signs, and license plates were changed to match those found in New York.
J.K. Simmons originally filmed scenes as J. Jonah Jameson for this movie. In the time that elapsed between the film's original shoot and the production of Spider-Man: No Way Home (2021), it became evident to the filmmakers that Morbius did not actually exist in the same universe as Simmons' version of J. Jonah Jameson. As a result, Simmons' scenes were removed from the film.
Matt Smith joined the film, after previously turning down other superhero film roles, due to director Daniel Espinosa's involvement and encouragement from his former Doctor Who (2005) co-star Karen Gillan, who portrays Nebula in the Marvel Cinematic Universe.
In the first crime scene, Agent Ramirez states that this was the weirdest crime after "that thing in San Francisco." This is a reference to Venom (2018). Later in the movie, Morbius states, "I am Venom" to a thug assaulting him. In the trailer, this line was followed by "I'm just kidding, it's Dr. Michael Morbius, at your service," but it was cut from the movie itself.