Amy Heckerling was inspired to write the film after her husband and writer Neal Israel started playfully talking in a different voice to pretend what their new baby would say. Her husband also has a cameo as Kirstie Alley's character's boss.
In the scene where James (John Travolta) is pouring out his soul to Mikey, he talks about anecdotes and advice his grandfather used to tell him. He says that one of his favorites was "If all your buddies jumped off the Brooklyn Bridge, does that mean you gotta too?" One of the most famous scenes in another John Travolta film "Saturday Night Fever" is of Tony (John Travolta) and of his friends fake-jumping off the Verrazano-Narrows Bridge.
Geena Davis was considered for the role of Mollie. But Davis turned it down, because she couldn't handle shooting a movie involving a birth sequence, especially with her birth sequence in The Fly (1986).
Two scenes are adages to Kirstie Alley's previous films. The first one is during her labor scene where she says she'll go to summer school to makeup for dropping out of Lamaze classes. She was in the movie Summer School with Mark Harmon. The other is where she's talking about Dr. Spock's book. She played in Star Trek with Mr. Spock.