Luft made her show Business debut at age 11 singing "Santa Claus Is Coming to Town" on the 1963 Christmas episode of Garland's CBS television series, The Judy Garland Show. Siblings Liza Minnelli and Joey Luft also appeared.

Luft made her Broadway debut in 1971 at the Shubert Theatre as a replacement cast member in the musical Promises, Promises, adapted from the classic 1960 Billy Wilder film The Apartment. It is best known for the hit song "I'll Never Fall in Love Again".

Luft starred in the 1981 national tour of They're Playing Our Song and in 1982 she played Paulette Rebchuck in Grease 2. In 1983, she played Peppermint Patty in the Off Broadway production of Snoopy!!! The Musical, a sequel to You're a Good Man, Charlie Brown. Later that year, she costarred in Extremities with Farrah Fawcett.

In films, Luft has appeared in Grease 2 (1982), Where the Boys Are '84 (1984), 54 (1998), and My Giant (1998). She and her brother, Joey, made cameo appearances in the 1963 film I Could Go On Singing.

Luft appeared as Nurse Libby Kegler on the CBS television series Trapper John, M.D. during the final season of 1985–1986 and also appeared as Patti Bristol in a 1985 episode of Murder, She Wrote entitled 'Broadway Malady'.

From 1992 through 1994, Luft played Adelaide in the American and world tour productions of Guys and Dolls. In 1996, she appeared in an Irish production of Follies in Dublin with Mary Millar, Alex Sharpe, Christine Scarry, Aidan Conway, Enda Markey, Dave Willetts and Millicent Martin. In 2002, she starred as Mama Rose in a University of Richmond school production of Gypsy.

Luft is the author of the 1998 book Me and My Shadows: A Family Memoir. Among its revelations is that she had an affair with Barry Manilow in 1971. In 2001, it was adapted as an Emmy-winning TV miniseries Life with Judy Garland: Me and My Shadows. It stars Judy Davis as the adult Judy, Tammy Blanchard as the teenage Judy, Hugh Laurie as Vincente Minnelli, Victor Garber as Sid Luft, and Marsha Mason as Ethel Gumm. Luft is the co-author (film Historian Jeffrey Vance is credited as the other co-author) of the 2018 book, A Star Is Born: Judy Garland and the Film That Got Away.

In October 2007, Luft released her debut CD Lorna Luft: Songs My Mother Taught Me in the United Kingdom. Produced by Barry Manilow and her husband Colin R. Freeman, the album celebrates Garland's music. In 2005 she toured Ireland with her stage show, Songs My Mother Taught Me. In June 2006, she surprised audiences at Carnegie Hall by performing a duet with Rufus Wainwright on the song "After You've Gone" at the end of Wainwright's tribute concert of Garland's triumphant 1961 comeback at Carnegie Hall.

In April 2009, Luft completed a successful UK tour of the critically acclaimed Hugh Whitemore play Pack of Lies, in which she played the role of Helen Kroger. She starred alongside Jenny Seagrove, Simon Shepherd and Daniel Hill. In May 2009, she appeared in W magazine as a special guest performer for the acclaimed avant-garde Theo Adams Company's latest project, 'Performance', photographed by David Sims. In July 2009, she appeared at the Mermaid Theatre, London to record for the radio series Friday Night is Music Night. Lorna Luft and Friends – A Tribute to Judy Garland also featured John Barrowman, Frances Ruffelle and Linzi Hateley.

On December 17, 2012, Luft discovered a lump on her right breast. "I was in total denial", she said. Three weeks later, her radiographer informed her that she had grade-2A breast cancer. She called her close friend, Barry Manilow, who connected her with cancer specialist David Agus. After reviewing the tests, Agus told her, "I’m looking at your biopsy and I can tell you right now, Lorna, you're going to be okay." To save her breast, she opted for a lumpectomy followed by adjuvant chemotherapy and radiation. She completed her final chemotherapy treatment in 2013.

In June 2015, Luft revealed that her cancer had reemerged. Consequently, the UK tour of Judy - The Songbook of Judy Garland concluded early on July 11, and she returned to the United States for surgical treatment.

In March 2018, Luft was diagnosed with a brain tumour after collapsing following a London performance.

Luft soon joined the family act on a summer concert tour, the highlight being Garland’s third and final appearance at New York City's famed Palace Theatre on Broadway in 1967. In this month-long engagement, Garland "shared" the bill with Luft (then 14 years old) and Joey (12 years old). The show was recorded live and released on ABC Records as Judy Garland: At Home At The Palace.