Set in New York City, the plot involves the interaction between two women – a bored housewife and a bohemian drifter – linked by various messages in the personals section of a newspaper.

Some critics labeled Desperately Seeking Susan as one of the best US films of the year, including Vincent Canby from The New York Times, and eventually, of the decade by publications such as NME and Rolling Stone.

[6] Roberta Glass, an unfulfilled housewife from Fort Lee, New Jersey, is fascinated by the messages between lovers Susan Thomas and Jim Dandy in the personals section of a New York City tabloid.

Meanwhile, in an Atlantic City hotel, the itinerant Susan reads the section after a tryst with mobster Bruce Meeker.

Arriving in New York City, Susan dons one of the earrings and stashes the other in her suitcase in a Port Authority locker.

She asks to stay with her friend Crystal, a magician's assistant at the Magic Club, and learns that Meeker was killed at the hotel.

Hoping to spot the lovers, Roberta goes to Battery Park and sees Jim reunite with Susan before leaving with his band for Buffalo.

Dez arrives on a moped and rescues Roberta, who falls and hits her head, causing her to lose her memory and her bag.

When they arrive, they find Dez's ex-girlfriend, Victoria, and her new partner taking most of the apartment items, leaving him with practically nothing, including no couch.

Roberta eventually arrives at the Magic Club, narrowly missing Susan who has been released from jail and discovered her suitcase is gone.

At Gary's house, Susan sees a television report about Meeker and Nolan stealing the earrings, which once belonged to Nefertiti.

Dez leaves as Roberta tries to explain the events of her disappearance to Gary, finally voicing her unhappiness and ending their marriage.

Seidelman employed a wide range of artists in small appearances, including comedian Rockets Redglare as a taxi driver; former member of the Shirts Annie Golden as a band singer; performance artist Ann Magnuson as a cigarette girl; musician and painter John Lurie as the neighbor saxophonist; La Mama and Living Theatre member Shirley Stoler as a jail matron; Ambitious Lovers member Arto Lindsay as the newspaper clerk who places the "seeking" ads; Ensemble Studio Theater founder Curt Dempster as coffee shop manager, Nick; and future Seinfeld-writer Carol Leifer as a party guest.

Orion chairman Mike Medavoy initially campaigned for Barbra Streisand to play the title role.

[10] It also has an alternate ending included on the DVD, in which Susan and Roberta are invited to Egypt after helping return the earrings.

Seidelman cut this scene, saying that it was unnecessary and audiences at the test screenings thought the film should have already ended much earlier (as explained on the DVD).

Separated-at-birth triplets Robert Shafran, Eddy Galland and David Kellman have a cameo role, reportedly at Madonna's personal invitation.

In some territories, it was included on a 1985 reissue of Like a Virgin, but in the United States it was only released as a double A-side 12″ single with "Angel".

The website's consensus reads: "Desperately Seeking Susan works with its fairy tale depiction of New York and the fun, frothy chemistry generated by its two leads.

[21] Roger Ebert of The Chicago Sun Times gave the film three stars out of a possible four, saying it was essentially a screwball comedy, which "bopped around New York, introducing us to unforgettable characters".

[23] In similar remarks, film critics like James Monaco deemed it as "Madonna's best role", playing a character "loosely based on herself".

[43][44] In the video rental charts, the film debuted at number 7 and climbed to the first-position on the issued dated September 28, 1985.

[48] In January 1986, the film was certified Gold by the International Tape/Disc Association, denoting 75,000 copies or sales totaling $3 million at retail.

[56] Movie's costume designer, Santo Loquasto reportedly sought inspiration for Susan's wardrobe in Madonna's own closet.

[57] In 2019, Laird Borrelli-Persson from Vogue stated, "fashion's so corporate these days, Desperately Seeking Susan reminds us that clothing is a personal signifier of identity connected to place and time.

[8] He also said, at the time, and even somewhat by today's standards Desperately Seeking Susan "was revolutionary in that it featured two female leads and was written, produced, and directed by women".

[6] The film was developed into a stage musical that premiered at London's Novello Theatre on November 15, 2007, following previews from October 16, 2007.

The production was directed by Angus Jackson, with book and concept by Peter Michael Marino and sets and costumes by Tim Hatley.

[70] Marino presented his solo comedy Desperately Seeking the Exit, which is based on his experiences, at the 2012 Edinburgh Festival Fringe.