Kusama graduated from Ladue Horton Watkins High School in St. Louis, Missouri. In 1990, she earned a BFA in Film & TV from New York University's Tisch School of the Arts.
While working for Sayles, she continued to write screenplays. In 1992, Kusama started boxing at Gleason's Gym in Brooklyn, training with Hector Roca. She began collecting ideas for Girlfight, but didn't start writing it until two years later.
After financing fell through shortly before shooting began, Girlfight was fully financed by film-maker John Sayles, for whom she worked as an assistant at the time and who served as a mentor. The film was released in 2000 and won the Director's Prize and the Grand Jury Prize at the Sundance Film Festival, as well as the Prix de la Jeunesse at the Cannes Film Festival. The independent feature film with a budget of around US$1 million was critically well received. However, it brought in only US$1,667,000, which was considered a poor return; it has since become a classic Example of the "Sundance Effect".
In 2005, Kusama directed her second film, Æon Flux, a Paramount Pictures studio production that starred Charlize Theron and had a budget of US$62,000,000. The film had been ushered through production by Paramount studio chief Sherry Lansing but during post-production Lansing left, which resulted in the film being recut and reworked, with significant changes from Kusama's original vision. Following this experience, Kusama said she would never again work on a film in which she doesn't have control of the final cut. Its worldwide gross was estimated at around US$52,000,000.
Kusama married Screenwriter Phil Hay in October 2006. They have a son. Although they had known each other since meeting at Sundance when Girlfight premiered in 2000, it wasn't until they worked together on Æon Flux that they began dating.
In 2009, Kusama directed the film Jennifer's Body, which was written by Diablo Cody. The film grossed approximately US$31,000,000 on a budget of around US$16,000,000.
Starting in 2015, Kusama began working regularly in TV as a Director on shows like Halt and Catch Fire, Casual, and Billions. Kusama is slated to direct the upcoming adaptation of Breed, an adult horror novel by Scott Spencer under the pen name Chase Novak. The film will again be produced and written by Kusama's husband Phil Hay and his partner Matt Manfredi.
In 2017, Kusama directed a segment of an all female directed anthology horror film called XX.
