She had a long and prolific theater career and appeared in numerous musicals including Godspell, The Night That Made America Famous, The Magic Show, Working, Tintypes, and An American Daughter (for which she won her Tony Award for her portrayal of Dr. Judith Kaufman in 1997).

Thigpen also portrayed a radio DJ (shown only from the nose down) in Walter Hill's The Warriors (1979), and Leonna Barrett, the mother of an expelled student, in Lean on Me (1989), the story of American high school principal Joe Louis Clark.

Her last film, Anger Management (2003), starring Adam Sandler and Jack Nicholson, was released a month after her death and paid tribute to her in the end credits.

Thigpen was most known to television audiences for playing "The Chief" in the PBS children's geography game show Where in the World Is Carmen Sandiego?, which involved education, humor, and an occasional musical performance.

She also played Luna in the television show Bear in the Big Blue House and also appeared in many other television series during her career, most notably in a recurring role as Grace Keefer on the ABC daytime drama All My Children and a supporting role as Ella Mae Farmer, a crime analyst for the Washington, D.C., police department, on the CBS crime drama The District.

[6] She guest-starred in episodes of Gimme A Break!, Roseanne, Thirtysomething, The Cosby Show, L.A. Law, Law & Order, The Days and Nights of Molly Dodd, Homicide: Life on the Street, and Sesame Street, and was a regular cast member on the short-lived NBC sketch comedy series The News Is the News.

Thigpen recorded hundreds of QuickTime videos for cut-scenes in the games, and generally received praise for her performances in them; in reviewing the 1997 game, David Colker of the Los Angeles Times enjoyed the "on-screen presence of actress Lynne Thigpen", noting that she "brings a winning presence to her role,"[9] while Debbie Maria Leon of the New Straits Times wrote that "the urgency of the [confident Chief's] voice [gives] enough oomph to make [the player] go scurrying to restore history".

[12] Thigpen died of a cerebral hemorrhage on March 12, 2003,[13] in her Marina del Rey, California, home, outside of Los Angeles, after complaining of headaches for several days.