She went to appear in such blackout-oriented films as Tunnel Vision (1975) and Chesty Anderson USN... (1976), and as a regular on the 1976 TV series Fun Factory, a combination quiz show/audience participation/sketch-comedy outing. Thomas achieved stardom in the role of no-nonsense police officer Lucille Bates on TV's Hill Street Blues (1981-87), winning a 1985 Emmy for her work on the series. Never one to shy away from any personal or professional risk, she plunged into TV directing in the late 1980s, helming such films as Only You (1991) and such made-for-TV flicks as My Breast (1994). In 1993, Thomas won her second Emmy, this time for her direction on the cable sitcom Dream On. As of this writing, Betty Thomas' biggest directorial success has been the 1995 box office bonanza The Brady Bunch Movie. She then made a pair of comedies about the media. Her made for cable adaptation of The Late Shift covered the retirement of Johnny Caron and the battle between Jay Leno and David Letterman to take over The Tonight Show. Thomas also directed Private Parts, the biopic of radio personality Howard Stern. Teaming with Eddie Murphy, Thomas scored a solid box-office hit with {#Dr. Dolittle. She attempted a change of pace with Sandra Bullock with the addiction comedy/drama 28 Days. She had her hand in a pair of summer hits acting as producer on the Charlie's Angels films, but also produced the flop Surviving Christmas.

She helped bring another television show to the big screen by joining Owen Wilson and Eddie Murphy in I Spy. In 2006 she helmed the dark high school comedy John Tucker Must Die.