Ralph has appeared in a number of movies during her career. In 1991, she received an Independent Spirit Award for Best Supporting Female for her role in the drama film To Sleep with Anger. Her other film credits include The Mighty Quinn (1989), The Distinguished Gentleman (1992), Sister Act 2: Back in the Habit (1993), and Deterrence (1999). On television, Ralph starred from 1986 to 1989 in the syndicated sitcom It's a Living, and later had the leading roles in the short-lived ABC sitcom New Attitude (1990), and CBS medical drama Street Gear (1995). From 1996 to 2001, she starred as Dee Mitchell in the UPN sitcom Moesha, and from 2013 to 2015 as Maggie Turner in the Nick at Nite sitcom Instant Mom. She was also a guest host of the popular weekly music series Soul Train in the mid 90's.
In July 2004, Ralph was inducted as an honorary member of Delta Sigma Theta sorority at the 47th National Convention in Las Vegas, Nevada. In May 2008, Ralph was awarded an honorary doctorate of humane letters from Tougaloo College after giving the commencement address.
Sheryl Lee Ralph released her first book Redefining Diva: Life Lessons from the Original Dreamgirl (2012) by Simon & Schuster. In 2016 she played Madame Morrible in Wicked on Broadway.