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 (1977), 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 (1987) with Mark Harmon. The other is where she's talking about Dr. Spock's book. She played in Star Trek II: The Wrath of Khan (1982), with Leonard Nimoy as Captain Spock.
Amy Heckerling first pitched the movie to Disney. Disney CEO Michael Eisner felt that it was too sexual for them even for their Touchstone Pictures banner. Paramount Pictures, Warner Bros, Orion Pictures, 20th Century Fox and Universal Studios also passed on it too. Ultimately it was TriStar Pictures who liked the script and green lit the film with a $7 million budget.
Although the movie takes place in New York, the filmmakers decided to shoot the movie on location in Vancouver, British Columbia, Canada as an attempt to save money. Some parts of the city of Vancouver were dressed up to look like the streets of New York.
The role of Harry (Mollie's accountant date) was originally meant as a cameo role for Amy Heckerling's friend and fellow director John Landis. But Landis turned it down as he didn't really like working on movies involving with kids, especially after what happened with him during the making of Twilight Zone: The Movie (1983).
Robin Williams, was considered for the voice of Mikey. But Williams' agent wanted too much money, which was double the film's production budget. However, he would co-star with John Travolta in the Disney movie, Old Dogs (2009).