Lifford graduated from the University of Santa Monica. She began her career in 1980s, appearing on television shows include Hill Street Blues, Cagney & Lacey, and Murder, She Wrote. From 1983 to 1988, she had the recurring role on Knots Landing. In film, she made her debut in The Ladies Club (1986). The following years, she had appeared in films include Nuts (1987), Colors (1988), Paris Trout (1991), Grand Canyon (1991), Letters from a Killer (1998), Panic (2000), Pay It Forward (2000), Joe Somebody (2001), Blood Work (2002), Hostage (2005), and Catch and Release (2006).

Lifford played the leading role as single mother Joan Mosley in the critically acclaimed but short-lived Fox comedy-drama series, South Central (1994). In addition to her leading role on South Central, Lifford was regular cast member on the short-lived NBC drama, Crisis Center (1997). She had number of starring roles on the made-for-television movies, include The Ernest Green Story (1993), Run for the Dream: The Gail Devers Story (1996) playing Jackie Joyner-Kersee, Mandela and de Klerk (1997) as Winnie Mandela, The Temptations (1998), and The Loretta Claiborne Story (2000) starring Kimberly Elise.

During her career, Lifford had guest starring roles in over 50 shows, include Touched by an Angel, Star Trek: Deep Space Nine, Any Day Now, NYPD Blue, NCIS, ER, and Nip/Tuck. She also had the recurring roles on Family Law (1999-2001), CSI: Crime Scene Investigation (2004-2005), Lincoln Heights (2007-2009), Parenthood (2010-2015) as Joy Bryant's mother, and Scandal (2015).

In 2016, Lifford was cast in her first series regular role as of 1990s, in the Oprah Winfrey Network drama Queen Sugar produced by Ava DuVernay and Oprah Winfrey. She plays the role of Violet Bordelon, the aunt to the Bordelon siblings Nova (Rutina Wesley), Ralph Angel (Kofi Siriboe) and Charley (Dawn-Lyen Gardner). Violet is a spunky woman involved in a long-term relationship with a younger man (played by Omar Dorsey).