Grier came to prominence with her titular roles in the films Coffy (1973) and Foxy Brown (1974); her other major films during this period included The Big Doll House (1971), Women in Cages (1971), The Big Bird Cage (1972), Black Mama White Mama (1973), Scream Blacula Scream (1973), The Arena (1974), Sheba, Baby (1975), Bucktown (1975) and Friday Foster (1975).

[10] Grier spent part of her upbringing on her maternal grandparents' sugar beet farm in rural Wyoming, where their ancestors had homesteaded after fleeing west via the Underground Railroad to escape slavery.

Grier moved to Los Angeles, California, in 1967, where she was initially hired to work the switchboard at American International Pictures (AIP).

[14] Grier played similar characters in the AIP films Foxy Brown (1974), Sheba, Baby and Friday Foster (both 1975).

She acquired progressively larger character roles in the 1980s, including a druggie prostitute in Fort Apache, The Bronx (1981) and a witch in Something Wicked this Way Comes (1983).

In 1985, Grier made her theatrical debut in Sam Shepard's Fool for Love at the Los Angeles Theatre Center.

She had a recurring role on Miami Vice from 1985 to 1989, and made guest appearances on Martin, Night Court and The Fresh Prince of Bel Air.

Her role in Rocket Gibraltar (1988) was cut due to fears by the film's director, Daniel Petrie, of "repercussions from interracial love scenes".

Grier occasionally guest-stars in such television series as Law & Order: Special Victims Unit (where she is a recurring character).

In 2010, Grier began appearing in a recurring role on the hit science-fiction series Smallville as the villain Amanda Waller, also known as White Queen, head agent of Checkmate, a covert operations agency.

[18] Essence magazine wrote in 2012,"So revolutionary were the characters Grier played that women reportedly would stand on chairs and cheer".

[22] In April 2022, Turner Classic Movies (TCM) announced the fourth season of their podcast, The Plot Thickens, would focus on Grier's life and career.

[22] Grier met the comedian Richard Pryor through her relationship with Prinze; they began dating after they were both cast in 1977's Greased Lightning.

[30] Grier was formerly romantically linked to Jimmie "Big Wheel" Wheeler, a famous boxing promoter; Soul Train host Don Cornelius;[31] and basketball player Wilt Chamberlain.

[36] For her the culture-shaping effect of cultural contributions made throughout her career,[37] Grier was recognized with a lifetime achievement award at the 2024 Toronto Black Film Festival.

[38] For Valentine's Day 2024, Quentin Tarantino paid homage to Grier with the opening of a Los Feliz coffee shop, carrying the namesake of the 1973 American-culture-shaping character she famously portrayed in Coffy.