The series focuses mainly on newlyweds Paul Buchman, a documentary filmmaker, and Jamie Stemple Buchman, a public relations specialist, as they deal with everything from humorous daily minutiae to major struggles. Near the end of the show's run, they have a baby daughter, whom they name Mabel. They live in Greenwich Village in Lower Manhattan. The 2019 limited series focuses on Paul and Jamie as empty nesters as Mabel starts college at New York University, five blocks away.

Helen Hunt and Paul Reiser were paid $1 million per episode for the last season (with their contracts calling for them to be paid equally). However, ratings fell sharply that year as the series was shuffled away from its Tuesday slot to prop up a fledgling Monday night line-up of comedies on NBC.

The show's theme song, "Final Frontier", was composed by Reiser and Don Was. It was originally performed by Andrew Gold, with a later version covered by Anita Baker, and finally Lyle Lovett and Kecia Lewis, who both had minor acting roles in the series.

Exterior views of buildings were filmed in Manhattan. Paul and Jamie's New York City Apartment was located at 5th Avenue and 12th Street. The Old Town Bar and Restaurant on 45 E. 18th Street was used for the fictional Riff's Restaurant in the series.
In April 2018, it was announced that Sony Pictures Television would revive the show with the two lead actors reprising their roles, though Reiser expressed doubt about it in July 2018. In September 2018, Reiser stated that the revival was still on the table, but that "the studio needs to figure out if they know how to do it."

On March 6, 2019, the series was revived for an eighth season by Spectrum Originals, described as a 12-episode limited series, with Reiser and Hunt confirmed to reprise their roles. On September 5, 2019, it was announced that the first six episodes of the revival would premiere on November 20, 2019, and another six episodes would be released on December 18, 2019. The series is available in a traditional manner in Canada, with its episodes airing on the CTV Comedy Channel.

Many of the main and recurring cast members reprised their roles for the revival, which ignored the events of the season 7 finale (a flash-forward story that told how the Buchmans would fare over the next 20+ years). The most notable former main cast member not to reprise her role was Leila Kenzle, who played Jamie's best friend, Fran Devanow. Kenzle retired from acting in 2003 and became a psychotherapist. Fran's husband, Mark, does return in the revival, but the character is now remarried.

Mad About You has had numerous connections to other NBC sitcoms set in New York City, as well as various other programs.

Friends (owned by Warner Bros. Television): Lisa Kudrow played the recurring role of Ursula, a flaky waitress at Riff's Bar, a local restaurant that Paul and Jamie frequented. Kudrow went on to star in the NBC sitcom Friends, playing the also somewhat flaky character of Phoebe Buffay, and for a time both series shared the same Thursday night line-up. While not originally intended, the characters of Ursula and Phoebe were later found to be identical twin sisters. In a Friends episode ("The One With The Two Parts", 1st Season), as part of a night of NBC sitcom crossovers, Jamie and Fran walk into Central Perk and mistake Phoebe for Ursula. Hunt and Kenzle were not identified on screen as Jamie and Fran. In the season three episode "Pandora's Box", Jamie causes a citywide power blackout in New York City, and the effects of the blackout are seen in the Friends episode, "The One with the Blackout", and there was also a blackout in the episode "Birthday in the Big House" of the NBC sitcom Madman of the People. All three episodes originally aired during the evening of November 3, 1994, alongside a Seinfeld episode which did not incorporate the blackout premise.

Seinfeld: In one episode ("The Apartment", 1st Season), Paul, pressured by Jamie, decides to sign over the lease of his old "bachelor pad" to the current tenant who is subleasing. When the tenant is revealed to be Cosmo Kramer (Michael Richards) of Seinfeld, Paul asks Kramer "What ever happened to that Jerry guy who used to live there?" Seinfeld, however, twice contradicted this connection, once even featuring a running joke about George's distaste for his fiancée Susan's fondness for watching Mad About You. In the Mad About You season seven episode "Season Opener", Paul, under the effects of Viagra, ran into Jerry Seinfeld in the street, who tells Paul to go away. At this point in Seinfeld's chronology, Jerry Seinfeld was supposed to be in prison.

The Dick Van Dyke Show: Carl Reiner reprised the role of Alan Brady from the 1960s sitcom. The episode made several references to the older show, such as Jamie at one point crying and whining "Oh, Paul!" – a take on Mary Tyler Moore's character Laura Petrie's frequent refrain "Oh, Rob!" – Ten episodes earlier, Paul almost trips over a box and says, "Get me, I'm Dick Van Dyke."

Style & Substance: In the 2019 revival ("Real Estate for Beginners", 8th Season), Jean Smart appeared as Chelsea Stevens-Kobolakis, a controlling, abrasive, short-tempered character that she had previously portrayed in showrunner Peter Tolan's 1998 series. Paul and Jamie attend a weekend team-building workshop that Chelsea hosts, mistakenly thinking that it's the marriage counseling seminar which is being held in a nearby room.