Writer David Simkins conceived the film while working at New World Pictures after reading the script for Ferris Bueller's Day Off, wanting to make a teen film in the vein of that movie and After Hours about a series of misadventures over a limited time period. New World passed on it, so Simkins wrote the script and sold it to Paramount instead.

Paramount Pictures held a right of first refusal on the project but demanded that Molly Ringwald be cast in the lead; when she turned it down, the studio reportedly proposed Cher and Bette Midler as alternatives before Touchstone Pictures took over the film after Disney secured $300 million in financing from Silver Screen Partners.

Over 150 actresses auditioned for the lead role across Dallas, Florida, New York City, Toronto, Chicago, and Los Angeles, including Valerie Bertinelli, before director Chris Columbus cast Elisabeth Shue, who was a Harvard University student at the time.

For his directorial debut, Chris Columbus reviewed about 100 scripts and chose Adventures in Babysitting because he felt comfortable with its scale.

The idea for the singing scene at the blues club came from director Chris Columbus himself, according to screenwriter David Simkins.

Principal photography began in Toronto on January 5, 1987, with many scenes there standing in for Chicago; production designer Todd Hallowell added trash to simulate Chicago streets and reconstructed two stories of the Associates Center skyscraper for the iconic shot of the characters dangling out of it.

Cinematographer Ric Waite shot the film using techniques more typical of a drama than a comedy in order to highlight the film's unpredictable tone.

In a 2021 interview, Elisabeth Shue said performing the 'Babysitting Blues' song, written by pop songwriter Mark Mueller and Robert Kraft, was one of her favorite experiences of all time.

Adventures in Babysitting was the first Walt Disney movie to receive a PG-13 rating.