Griffis attended the North Carolina School of the Arts, where she earned a BFA. She started acting in theatre at the age of seven. As an adult, she has played the roles of Lady MacBeth and Lady Anne; and appeared in the stage plays Angels in America, Proof, Intimate Apparel, Collected Stories, Dinner with Friends and Dark at the Top of the Stairs.

Griffis' first big screen film role was in the 1992 drama film Love Field, where she played Jacqueline Kennedy, the former First Lady and widow of the assassinated President John F. Kennedy. Though her first role, her first movie role outside of theater was actually in the television movie A Mother's Right: The Elizabeth Morgan Story, a biographical film about Elizabeth Morgan. Aside from film, she made numerous appearances on made for TV films and series – including In the Heat of the Night. Griffis is known for making the roles she is offered both memorable and intriguing.

Griffis has been in over 30 feature films, and 33 TV films and series. Griffis is also a notable professional actress on stage. She worked seven seasons with The North Carolina Shakespeare Festival, 5 seasons with Charlotte Rep, as well as appearing at Saint Louise Repertory, Alabama Shakespeare Festival, Theatre by the Sea (Portsmouth, NH), The Alliance Theatre, Theatrical Outfit, and 3 Seasons with Actors Theatre of Atlanta.

Griffis is known for her work in Love Field, Runaway Jury, Walk the Line, Road Trip, and Year One. In 2000, she appeared in Songcatcher, as the wife of the coal company boss named Ambrose, Clementine McFarland. Among her most recent roles is the feisty Lenore Baker in Lifetime's hit television drama, Army Wives. In addition, she made memorable appearances in American Summer and the film remake One Missed Call.