[5][6] She was raised in Manhattan's East Village, attending school at Friends Seminary in the city's Gramercy neighborhood, where she graduated in a class of 57 students.

She plays Stephanie, a marijuana-smoking "popular girl" from New York City, in Sundance Audience Award-winning mid-1990s period piece film The Wackness, which was released in the U.S. on July 3, 2008, and stars opposite Josh Peck.

[2] Thirlby was cast in the Judd Apatow-produced, David Gordon Green-directed stoner comedy Pineapple Express as the girlfriend of Seth Rogen's character, but was replaced by Amber Heard after rehearsing for the film.

[9] She made her stage debut in Farragut North, a play by Beau Willimon at the Atlantic Theater Company in New York City.

She voices promotional video excerpts from the novel Thirteen Reasons Why by Jay Asher which, since October 2008, have regularly been posted to YouTube.

[13] Thirlby starred in the Russian science-fiction film The Darkest Hour, released in 2011, directed by Chris Gorak, and produced by Timur Bekmambetov.

[15] That same year Thirlby agreed to participate in iO Tillett Wright's Self-Evident Truths Project, an effort to capture the diversity of the LGBTQ+ in the United States through photography.