Mordden was raised in Pennsylvania, in Venice, Italy, and on Long Island, and is a graduate of Friends Academy in Locust Valley, New York, and the University of Pennsylvania. He at first sought a career in show business, working as music director on off-Broadway and in regional theatre, and enrolling in the BMI Lehman Engel Musical Theater Workshop run by Lehman Engel. As both composer and lyricist, Mordden wrote musicals based on William Shakespeare's Measure For Measure and on Max Beerbohm's Zuleika Dobson, but he ended up earning his living as a writer of English prose.

His stories, novels, essays, and non-fiction books cover a wide range of topics including the American musical theater, opera, film, and, especially in his fiction, the emergence and development of contemporary American gay culture as manifested in New York City. He has also written for The New Yorker,including fiction, Critic At Large pieces on Cole Porter, Judy Garland, and the musical Show Boat, and reviews of a biography of the Barrymores and Art Spiegelman's graphic novel Maus.

His best known fictional works are the inter-related series of stories known collectively as the "Buddies" cycle. In book form, these began with 1985's I've a Feeling We're not in Kansas Anymore. The fifth in the series, 2005's How's Your Romance?, is subtitled Concluding the "Buddies" Cycle. Together, the stories chronicle the times, loves, and losses of a close-knit group of friends, men who cope with the challenges of growing up and growing older. In this circle of best friends, teasing putdowns become performance art, but none of the friends ever attacks any other friend's sensitive spots. Mordden thus breaks away from the gay model proposed by Mart Crowley's play The Boys in the Band, in which supposed best friends assault one another relentlessly in a style that has bedeviled gay art ever since, for instance in the television series Queer as Folk. Mordden's ideal of gay friendship presents men who genuinely like themselves and one another. They are unique in gay lit in that they respect the limits of privacy. This explains their devotion to one another: this "family" is a safe place.

In 1995, Mordden produced an epic novel, How Long Has This Been Going On?, following the lives of a diverse group of men and women from 1949 to 1991. All but one of the principal characters are gay or lesbian. Mordden's own favorite among his works of fiction is The Venice Adriana of 1998, which uses the life and art of the opera soprano Maria Callas to question whether we are trapped by fate or free to invent a destiny. In a Nabokovian game meant for opera lovers, the novel's plot and characters reflect the plot and characters of Francesco Cilea's opera Adriana Lecouvreur. Mordden's least well-known work is A Bad Man Is Easy To Find, published in 1989 under the pseudonym of M. J. Verlaine. Though the book aligns with the "Buddies" cycle in its structure of inter-related short stories, it is entirely about the lives of women, and has only one minor gay character. In 2008, Mordden published The Jewcatcher, a surrealistic novel set in Berlin from the end of the Weimar Republic to the last day of the European war. The many principal characters are a combination of Mordden's inventions and such real-life figures as Adolf Hitler, Marlene Dietrich, Raoul Wallenberg, Claus von Stauffenberg, and President Hindenburg.

Mordden's non-fiction includes seven volumes detailing the history of the Broadway musical from the 1920s through the 1990s, guides to orchestral music and operatic recordings, a cultural history of the American 1920s, and examinations of the phenomenon of the operatic diva and of the works of Rodgers and Hammerstein. He has written a number of books on film, including analyses of the influence of Hollywood studios and of the role of female film stars. In all his non-fiction, Mordden has been a pioneer among writers who bring their personal experience and even their personalities into discussion.

The New York Times spoke of Mordden as being among a group of "ruminators on popular culture" animated by "the gun-moll gesticulations of Pauline Kael, for whom responsiveness was everything."