Ann Nocenti is most noted as an editor for Marvel Comics, for whom she edited New Mutants and The Uncanny X-Men. She made her comics writing debut on a brief run of Spider-Woman (#47-50) and subsequently wrote a long run of Daredevil (1st series) #236-291 (minus #237) from 1986 to 1991, directly following on from Frank Miller's definitive Born Again storyline. She also wrote the 1986 Longshot limited series for Marvel, and in the same year produced the Someplace Strange graphic novel in collaboration with artist John Bolton. She wrote "the Inhumans Graphic Novel" in 1988. In 1993, she wrote the 16-issue run of Kid Eternity for the DC Comics imprint Vertigo.

In Incredible Hulk #291, published in September 1983 (cover date January 1984), Ann Nocenti made a cameo appearance, talking to Dr. Bruce Banner, in a history written by Bill Mantlo, drawn by Sal Buscema and inked by Carlos Garzón and Joe Sinnot. That time Ann Nocenti was Assistant Editor for Larry Hama on Incredible Hulk and X-Men.

She is noted for her left-wing political views which, particularly during her run on Daredevil, caused some controversy among some fans who didn't agree with her politics.

She created several popular characters, including Typhoid Mary, Blackheart, Longshot and Mojo, and wrote the 1998 X-Men novel Prisoner X.

Although Nocenti left comic books in the '90s after the industry sales collapsed, she later returned to the field, penning stories such as 2004's Batman & Poison Ivy: Cast Shadows.

In Ultimate X-Men, a reimagination of the X-Men comic, the character Longshot, who was invented by her, has the civil name Arthur Centino. His last name, Centino, is an anagram of Nocenti and a homage to Nocenti. The name Arthur is for the co-creator of Longshot Arthur Adams who was Ann Nocenti's artist on the Longshot Mini Series.

She edited High Times magazine for one year (2004) under the name Annie Nocenti and is the former editor of the screenwriting magazine Scenario.