This is one of the only two episodes in which the guest star uses a pseudonym instead of their real name (the other being Stark Raving Dad (1991)). Following the legal troubles surrounding that episode, the producers stated henceforce no pseudonyms would be allowed. As a result, all voice actors must use their true names in the credits.
The cast of the show flew to New York to record the episode with Dustin Hoffman. Yeardley Smith, said she grew as an actress after working with Hoffman that day.
In one particular scene, Maggie whimpers a little. Nancy Cartwright was asked to play Maggie and she accepted but she spotted her then-husband Warren Murphy and her daughter (who was a baby at the time) walking into the studio. She asked one of the directors if her baby could do the little whimpers for Maggie. The director said yes and Nancy Cartwright's daughter actually made the whimpers of little Maggie.
Jon Vitti mentioned on Twitter that the note Lisa receives at the end of the episode should've had an exclamation point at the end. He didn't catch it in the animatic and it still "haunts [him] to this day".
According to Jon Vitti, the episode was "very controversial" when it was being made because it "came at a point when the staff were just beginning to realize the comedy potential of the show, but we were trapped with these love stories, and just as the staff were starting to get frustrated with the love stories, along came 'Lisa's Substitute': the biggest, huggiest, warmest and fuzziest of them all."