Her class went to see a performance of A Day of Absence, featuring Douglas Turner Ward, a co-founder of The Negro Ensemble Company. It was the first time she saw professional black actors on stage. After graduating high school in 1967, she attended Northwestern University. She left after one year and went to work full-time as an operator at Illinois Bell. She got married and had a son. She transferred her credits to Loyola University-Chicago and earned a bachelor's degree in Theater Arts and Communications.

Caldwell planned on a teaching career and taught at Chicago High School of the Performing Arts. She also worked a year for the Chicago Council on Fine Arts as an artist-in-residence. While in Chicago Caldwell performed in local theatrical productions at the Body Politic, Court Theater, and Eleventh Street Theater. She went to New York in 1978 to audition for Uta Hagen's school HB Studio. While waiting to audition she saw an ad for The Negro Ensemble Company. After her audition at Hagen's school she took the subway to the NEC.

In her early twenties Scott married John Caldwell and had a son, Ominara. She was divorced in the early 1980s, and was married again (on her birthday) in 2004 to artist/photographer/director Dasal Banks. Banks suffered from cancer and died in May 2005. Caldwell completed her husband's final film, My Brothers and Me, a documentary created to raise awareness about prostate cancer among black men.

In December 1984, while working in Play of Giants, Caldwell was struck by a car while hailing a cab on Columbus Avenue in New York. She suffered a severe back injury and was unable to work for nearly two years. Her first audition after her recovery was for August Wilson's Joe Turner's Come and Gone. Her performance as Bertha Holly earned her a 1988 Tony Award. Soon after winning the Tony, she moved to southern California to work in television and film. She is extremely busy, working in several cities in the U.S., Canada, and South Africa, and continues to work in theater. She returned to Broadway in 1997 as the lead in Neil Simon's short-lived Proposals. After Proposals closed Caldwell performed the role of Leah, Little Augie's sister, in New York City Center's Encores! Great American Musicals in Concert production of St. Louis Woman.

In 2006, she made her Goodman Theatre debut in Regina Taylor's The Dreams of Sarah Breedlove. In 2011, she took on role of Lena Younger in the Ebony Repertory Theatre production of the Lorraine Hansberry classic A Raisin in the Sun. The play was directed by Phylicia Rashad. Caldwell, along with the entire cast, was nominated for the LA Stage Alliance 2011 Ovation Award for her work as Lena, for which she won the 2011 Los Angeles Drama Critics Circle Award.

Caldwell gives lectures and appears on panels concerning African American actors. In 2007, she participated in tributes to August Wilson at Goodman Theatre in conjunction with Congo Square Theatre Company in Chicago, and at St. Louis Black Repertory Company. In June 2008, she participated in the NAACP Theatre Awards Festival Actors on Acting panel. In June 2009, Caldwell moderated a panel of actors, Directors, and casting Directors discussing African American Images in Hollywood. In February 2010, she directed a staged reading of Standing On My Sisters' Shoulders for the Los Angeles chapter of Actors Equity Association.

Caldwell is an active member of Unite For Strength, the Screen Actors Guild coalition in favor of joining with AFTRA. On September 19, 2008, she won a seat as an alternate on the national board of Directors and Hollywood division board of Directors. Caldwell was elected to a second one-year term September 24, 2009. She served on the Seniors, Legislative, Women, Holiday Host, Honors and Tributes, and EEOC committees. In September 2010, she was elected to a one-year term on the national board of Directors. She served as the national chair of the Women's committee. In 2011, Caldwell is on the SAG national board of Directors ballot for a fourth consecutive year. She won a three-year term on the national and Hollywood boards. She will serve as national chair of Women, and Health care Safetynet committees.

In 2016, she was part of the six-part PBS Civil War drama miniseries "Mercy Street".