Witt was discovered by David Lynch, when she appeared on the first episode of That's Incredible in 1980, reciting Shakespeare's Romeo and Juliet. He then cast her for the movie Dune (1984), where she played Muad'Dib's young sister Alia of the Knife.

After this, Witt left Hollywood for six years, concentrating on school and music. She took piano lessons at Boston University and won several national and international classical piano competitions, including the Bartok-Kabalevsky International Piano Competition.

At age 14, Alicia earned her High School Diploma and, shortly thereafter, moved permanently to Hollywood with her mother (who is noted in the Guinness Book of Records for the world's longest hair) to pursue a career as a full-time actress. Soon, David Lynch, whom she refers to as a mentor, created the role of Gersten Hayward in his hit series Twin Peaks especially for her. He would again cast her in the segment Blackout in his short-lived HBO series Hotel Room. That was the last collaboration between the two for the time being. At that time, Alicia was already supporting herself playing the piano at the Regent Beverly Wilshire Hotel.

She then went on to small parts in Mike Figgis' Liebestraum (in which her brother Ian also appears), the Gen-X drama Bodies, Rest & Motion and the TV-Movie The Disappearance of Vonnie.

In 1994, Alicia landed her first lead-role in a feature film playing the disturbed teenager Bonnie in Fun. She received the Special Jury Recognition Award at the Sundance Festival and was nominated for Best Actress at the Independent Spirit Awards. This performance made Madonna want Witt to be cast as her witch-lover in the first segment The missing ingredient of Four Rooms.

She was introduced to a larger audience playing the role of Zoey Woodbine, the daughter of actress Cybill Shepherd's character in the sitcom Cybill from 1995 to 1998. Between seasons, she kept on starring in feature films; Mr. Holland's Opus, Alexander Payne's abortion comedy Citizen Ruth, Passion's Way and Bongwater.

After Cybill got cancelled, Alicia got another leading role in the Scream-ish campus-horror Urban Legend and the animated feature Gen 13 which was never released, because the studio stopped funding before the completion of the movie.

2000 was a busy year for Witt with guest starring roles on the shows Ally McBeal and The Sopranos, the lead in the comedy Playing Mona Lisa, an instant-classic turn as an anal porn star in John Waters' Cecil B. Demented, and her stage-debut in Robbie Fox's musical The Gift at the now closed Tiffany Theater in Los Angeles, in which she played a high priced stripper with a disease.

In the years following, things got more quiet around Witt. She had a small part in Cameron Crowe's Vanilla Sky, which was in fact intended as a reference to her roles in Dune and Liebestraum. She also played a college graduate who talks about losing her virginity in the experimental Ten Tiny Love Stories and the trailer trash girl Barbie in American Girl, which was released to video in 2005.

She turned down the role of Mary Jane Watson in Sam Raimi's Spider-Man and made her comeback to mainstream cinema in the 2002 romantic comedy Two Weeks Notice.

In 2003 and 2004, she turned her back to Hollywood and lived in the UK most of the time, filming The Upside of Anger opposite Kevin Costner and starring as Evelyn in a new stage-production of Neil LaBute's The Shape of Things. In between these two gigs, she went to South Africa to shoot the German TV-Movie Kingdom in Twilight. She plays Kriemhild in this filmic interpretation of the epic poem Das Nibelungenlied, which was released in the US as Dark Kingdom: The Dragon King.

Witt currently resides in L.A. with her cat Jessie and her boyfriend, screenwriter Nathan Foulger.

On June 14, 2004, Witt modeled what is believed to be the most expensive hat ever made, for Christie's auction house in London. The Champrau d'Amour, designed by Louis Mariette, is valued at $2.7 million (US) and is covered in diamonds.