Her co-star on Mork & Mindy was Robin Williams, and she claimed that the most challenging part about the job had to keep her composure around his comedy. When the network insisted on sexualizing her character, Dawber refused, and Williams supported her decision against the network's wishes. They were close friends in addition to being coworkers. In her biography, she stated Williams was "such a nice person who had a gigantic heart." Garry Marshall, who initially selected Dawber for the role, said that Williams' "aim in life was to make Pam Dawber blush."

After the end of Mork & Mindy, Dawber landed another starring role as Samantha Russell on My Sister Sam's CBS sitcom in 1986. The show ran for 44 episodes and earned Dawber a second People's Choice Award for Favorite Female Performer in a New TV Program. The show was famous in its first season but dropped in ratings and was eventually taken off the air in 1988. In July of 1989, Dawber's former co-star, Rebecca Schaeffer, was shot and killed outside her apartment by an obsessive deranged fan. Dawber became a gun control advocate and filmed a public service announcement about violence prevention and the remaining former cast. She is also a national spokeswoman for Big Brothers and Big Sisters of America.

In addition to her well-known television roles, she has appeared in several movies, including Stay Tuned (1992) and I'll Remember April (1999). In 2014, she joined her former co-star Robin Williams in his comedy series The Crazy Ones, which was canceled not long after. Williams committed suicide only four months after the series' last episode. Later that year, Dawber participated in a one-hour TV special on PBS titled "Robin Williams Remembered" and was her first on-camera interview since the tragedy. She stated she was "completely and devastated." In 2017, Dawber appeared on The Odd Couple in a tribute to Garry Marshall, who was the one that plucked her from obscurity and brought her into the limelight.