In 1990 Stafford was cast in Fox soap opera Tribes. The show was canceled after 3-month airing on Fox. She later appeared in two plays directed by Charles Durning in Los Angeles stage, and co-starred in several small films.

In October 1994, Stafford began what was supposed to be a short term role of Phyllis Summers on the American CBS Daytime soap opera The Young and the Restless; however, her work impressed the producers and she was placed on contract. In 1997, Stafford left the series to pursue other career opportunities, and she was replaced by Sandra Nelson. In 1997 she was cast in Aaron Spelling primetime soap opera Pacific Palisades as lead character, but show was canceled after 13 episodes. She later guest-starred in Two Guys and a Girl, Diagnosis: Murder, and JAG. In film, Stafford appeared in 1999 thriller Double Jeopardy opposite Ashley Judd.

Stafford was born in 1965, in Chicago, Illinois. Her parents moved her and her older sister, Janine, to Montrose, California, where she was raised. After graduating from high school, Stafford chased after her dream of modeling. Stafford welcomed her first child, daughter Natalia Scout Lee, via her embryo and a gestational surrogate on Monday, December 21, 2009 In October 2015, Stafford welcomed her second child, a son Jameson Jones Lee.

In 2004, Stafford was a hockey correspondent for The Best Damn Sports Show Period. Stafford starred in Lifetime movie Like Mother, Like Daughter in 2007. In 2007, Stafford appeared on Tyra Banks' talk show to help Tyra through "soap opera school." In 2012 she appeared as Lauren on the web series The Grove, created by Crystal Chappell. She also guest-starred in Frasier, Charmed, and Ringer. She subsequently launched her web series, The Stafford Project, based on her personal life and struggles, with the first episode premiering on her YouTube Channel on August 5, 2013. The series received positive reviews from critics. Michael Logan of TV Guide appreciated the web series, calling it "terrific and audacious" and saying that "there's never a dull moment in the life of Michelle Stafford". Jamey Giddens of the entertainment website Zap2it said that Stafford is "as viable and fiery as ever", calling The Stafford Project "insanely-funny".

In 2014, Stafford returned to daytime television with the role of Nina Clay, the wife of Dr. Silas Clay (Michael Easton) on the ABC soap opera, General Hospital. Stafford’s long-rumored addition to the cast was made official when her character Nina, the presumed-dead wife of Silas, suddenly appeared at the very end of the episode on May 1, 2014. In 2015, she co-starred alongside Tom Sizemore in the independent film Durant's Never Closes.

In 2016, Stafford launched a skincare product line called Skin Nation. The products are said to be organic, natural, gluten free, vegan and cruelty free.