Before adapting the graphic novel to a film script, Heller had adapted the novel into an off-broadway play. She was selected as a 2012 Sundance Screenwriting Fellow and 2012 Sundance Directing Fellow, where she had submitted the script for the Sundance Writer and Director workshop. She then proceeded to direct a teaser for the film using grant money from the writer's workshop. The film received critical acclaim at Sundance, and was nominated for the Grand Jury Prize. The film also won the Grand Prix of the Generation 14plus at the Berlin International Film Festival in 2015.

Heller is married to entertainer Jorma Taccone. Together they have a son, Wylie Red Heller Taccone, born in December 2014.

The Diary of a Teenage Girl is Heller's debut film, that she both wrote and directed, which premiered at the Sundance Film Festival on January 24, 2015. The film later received a limited release in August 2015. It is based on the 2002 graphic novel titled The Diary of a Teenage Girl: An Account in Words and Pictures by Phoebe Gloeckner. The film stars Bel Powley as Minnie, a 15-year-old girl living in the San Francisco Bay Area in 1976 who begins an affair with her mother's 35 year-old boyfriend Monroe.

In January of 2018, it was announced that Heller would direct a biopic about Fred Rogers called You Are My Friend with Tom Hanks portraying Mr. Rogers.