Born in New York City, where she lived in the Chelsea Hotel until a move to Los Angeles when she was 11, Gaby Hoffmann began her career at age five, acting in commercials. At age six, she made her film debut in Field of Dreams alongside Kevin Costner. More films followed, including Sleepless in Seattle and The Man Without a Face, before Hoffmann made her television debut in 1994 in the short-lived series Someone Like Me. The next year saw Hoffmann in what is perhaps her best-known role: Samantha in the 1995 coming of age film Now and Then.

While Hoffmann kept busy with films during the late 1990s and early 2000s, she put her film career on hold after high school graduation in order to pursue a degree in literature at Bard College. She had roles in several plays in New York before gradually returning to the screen, with guest spots on shows including Private Practice, The Good Wife, and Homeland.

In 2014, Hoffmann appeared in four films, including the critically acclaimed movies Obvious Child and Wild. That same year, she landed a guest arc on Girls, and nabbed a regular role on Amazon's original series Transparent. Hoffmann plays Ali Pfefferman, the daughter of the transgender Maura Pfefferman, played by Jeffrey Tambor.