HIs most noted work to date is his six-book series collectively titled Tales of the City, the first portions of which were initially published as a newspaper serial starting in 1974 in a Marin County newspaper, followed by the San Francisco Chronicle and later compiled into a series of books published by HarperCollins (then Harper & Row). In 1978, Maupin produced a collection of his columns entitled Tales of the City at the urging of a friend at Harper & Row. Five more compilations followed in the 80s, ending with the last book, "Sure of You" in 1989. The Tales of the City books have been translated into ten languages and there are more than two million copies in print.

The first three books in the series have also been converted into three television miniseries, the first airing on the American television network PBS and the latter two on the American premium cable television channel Showtime.

Later works by Maupin, not part of the Tales series, include The Night Listener and Maybe The Moon. While Maupin has written on his website that it isn't entirely inconceivable that he would write another Tales of the City novel sometime in the future, he tells readers not to bank on it. Maupin's 2000 novel The Night Listener has been adapted into a movie that was screened at the 2006 Sundance Film Festival in late January. It has been suggested that The Night Listener bears resemblance to the Anthony Godby Johnson hoax.

In 2004, it was reported that he would pen a novel, to be published at least two years from then, "chronicling one day in the life of Michael Tolliver, now a 52 year-old gardener." Maupin later confirmed on his official message forum that the upcoming Michael Tolliver Lives! novel "is not a sequel to 'Tales' and it's certainly not Book 7 in the series." He also advised readers not to expect a reunion of their favorite characters though he conceded "one or two characters may emerge in the course of Michael's day."

Maupin grew up in North Carolina, where he attended the University of North Carolina at Chapel Hill. He is a veteran of the U.S. Navy, and once worked for the conservative television personality and later U.S. Senator Jesse Helms. His partner Terry Anderson is a former gay rights activist. His name, "Armistead Maupin", is an anagram of "is a man I dreamt up", which prompted some speculation that it was pseudonymous. The anagram myth was further inflamed when the BBC produced a documentary entitled Armistead Maupin Is a Man I Dreamt Up. On his website he says the anagram is only a coincidence; he was named for his father, a prominent lawyer in North Carolina.