Helen Hunt and Paul Reiser were paid $1 million per episode for the final season, though ratings dropped sharply after the show was moved from its Tuesday slot to bolster NBC's struggling Monday comedy lineup.

The theme song 'Final Frontier' was composed by Paul Reiser and Don Was, originally performed by Andrew Gold, later covered by Anita Baker, and finally by Lyle Lovett and Kecia Lewis, both of whom also had minor acting roles on the show.

Exterior shots were filmed in Manhattan, with Paul and Jamie's apartment located at 5th Avenue and 12th Street, and the Old Town Bar and Restaurant on 45 E. 18th Street standing in for the fictional Riff's Restaurant.

The Buchmans' dog Murray was played by Maui, a 58-pound dog found in a Castaic, California animal shelter by Hollywood animal trainer Boone Narr and trained primarily by Betty Linn, who had previously worked in TV commercials and as backup dog for the film Bingo.

Baby Mabel was played by multiple performers over the years, including twins Alyssa and Justin Baric, later Carter and Madison Gale, with Meredith Bishop, Cara DeLizia, and Janeane Garofalo playing older versions of the character in different episodes.

Lisa Kudrow played waitress Ursula at Riff's in Mad About You while simultaneously starring as Phoebe Buffay on Friends; the two characters were later revealed to be twin sisters, and a crossover scene had Jamie and Fran mistake Phoebe for Ursula at Central Perk.

A citywide blackout caused by Jamie in the season three episode 'Pandora's Box' was tied into the Friends episode 'The One with the Blackout' and the sitcom Madman of the People, with all three episodes airing on the same night, November 3, 1994.

In a crossover with Seinfeld, Paul signs over his old bachelor apartment lease to a tenant revealed to be Cosmo Kramer, though Seinfeld's own timeline later contradicted the connection by having George's fiancée Susan mock his dislike of the show Mad About You.

Carl Reiner reprised his role as Alan Brady from The Dick Van Dyke Show in an episode that referenced the earlier series, including Jamie mimicking Laura Petrie's catchphrase 'Oh, Rob!' as 'Oh, Paul!'

Leila Kenzle, who played Fran Devanow throughout the original run, did not return for the 2019 revival because she had retired from acting in 2003 to become a psychotherapist.

The 2019 revival, produced as a 12-episode limited series for Spectrum Originals, ignored the events of the original series' flash-forward finale, which had depicted the next twenty years of the Buchmans' lives.