She moved to L.A. when she was 18 years old. She met Farrell at a benefit concert a year later, at which his band Psi Com was performing.

Throughout the course of her relationship with Farrell, Niccoli contributed heavily to the band's aesthetic. The cover of 1988 album, Nothing's Shocking, featured a sculpture created by Niccoli and Farrell for which Niccoli was the model. The 1990 album, Ritual Lo Habitual, featured a sculpture created by Niccoli and Farrell. She has also been credited with creating the band's early onstage aesthetic, including Catholic and Santerían imagery.

Niccoli directed the music video for the Jane's Addiction song Been Caught Stealing, for which she won an MTV Video Music Award in 1991 for Best Alternative Video, and a Foundations Forum Award for Best Music Video. Been Caught Stealing is rated number #48 on VH1's Best 100 Music Videos of all time.

With Farrell, Niccoli co-directed the film Gift, a 1993 experimental docudrama. The film features Farrell, Niccoli and the members of Jane's Addiction. Most of the filming took place during the recording sessions of Ritual de lo Habitual, in 1990.

Other Jane's Addiction videos to her credit are Classic Girl, Stop, and Mountain Song.