Witt has made television appearances in shows such as The Walking Dead, The Sopranos, Friday Night Lights, Twin Peaks: The Return, CSI: Miami, Supernatural, Justified and Orange Is the New Black.

[6] Her acting talent was recognized by director David Lynch in 1980, when he heard her recite Shakespeare's Romeo and Juliet on the television show That's Incredible!

[7] Witt's discovery by Lynch led to her casting as the "flame-haired" child in Dune (1984), as Paul Atreides's sister Alia; she turned eight during filming.

Her acting background led to small parts in Mike Figgis' Liebestraum in 1991 (her brother Ian also appears), the Gen-X drama Bodies, Rest & Motion (1993), and the television film The Disappearance of Vonnie (1994).

While playing that part from 1995 to 1998, she also had film roles in Stephen Herek's Mr. Holland's Opus,[9] Alexander Payne's Citizen Ruth,[2] Robert Allan Ackerman's Passion's Way (based on the Edith Wharton novel, The Reef) and Richard Sears' comedy Bongwater.

After Cybill was cancelled, Witt went on to leading roles in Jamie Blanks' horror film Urban Legend (1998),[2][9] and in Kevin Altieri/Touchstone Pictures' limited-release animated feature Gen13.

[citation needed] Witt filmed the Last Holiday (2006) and the thriller 88 Minutes (2007)[2] and joined the cast of Law & Order: Criminal Intent for the 2007–2008 season.

[2] Witt appeared as the character Elaine Clayton in Cowgirls 'n Angels (2012),[2] and in 2013, co-starred in the independent film Cold Turkey (opposite Peter Bogdanovich and Cheryl Hines); therein, she additionally performed an original musical piece over the end credits.

In 2014, in the fifth season of the FX series Justified she played Wendy Crowe, the brightest member of a Floridian crime family that gets entangled in the show's events in Kentucky.

[15] In April 2016, Witt appeared in two episodes of The Walking Dead;[16] the same month, it was announced that she would also be reprising her role as Gersten Hayward in the 2017 Twin Peaks series.

[19] Witt made her stage debut in 2001, at Los Angeles' historic Tiffany Theater, in Robbie Fox's musical The Gift, in which she played a high-priced, albeit disease-carrying, stripper.

[20][21] In September 2006, Witt returned to the London stage at the Royal Court Theatre, in the critically well-received Piano/Forte, wherein she was "well-cast" in portraying the stammering, emotionally damaged pianist Abigail, sister to "unloved attention-seeker" Louise (Kelly Reilly).

[22] Witt performed alongside Amber Tamblyn in Neil LaBute's play, Reasons to Be Pretty, at the Geffen Playhouse, which ran until August 31, 2014.

[42][43] On October 5, 2021, Witt released a book called Small Changes: A Rules-Free Guide to Add More Plant-Based Foods, Peace & Power to Your Life.

While having bested Dee Snider as "Doll" and Lou Diamond Phillips as "Mantis" (who was spared by Robin Thicke ringing the Ding Dong Keep It On Bell) on "WB Movie Night", she was eliminated in "Masked Singer in Space" alongside Melissa Joan Hart as "Lamp".