Hart, whose family includes her father, William Hart, her mother Paula Hart, her stepfather, television executive Leslie Gilliams, eight sisters and one brother, began acting early on. When she was a baby, she made her first commercial for a bathtub toy called Splashy. By the age of five she had already been in 25 commercials.
At the age of nine, she began acting on Saturday Night Live. She lasted there until 1986. During that time, she also appeared in many other shows, among them The Equalizer and the miniseries Kane and Abel.
In 1989, she auditioned for a Broadway production of The Crucible alongside Martin Sheen. She got the job of understudy to three of the young girls in the play and it paved the way for her to land the title role in the TV show Clarissa Explains It All. The Nickelodeon series, a comedy about a teen girl in everyday situations, became a big hit and aired for four seasons. This gave her much fame and recognition, making her a household name among American teenagers.
After the series was canceled, she decided to invest in higher education and went to New York University. But acting called upon her once again, and in 1994, she got the main role for the TV movie Sabrina the Teenage Witch, which eventually led to her also starring as Sabrina in a television series which lasted seven seasons. In between, she also worked on the series Touched by an Angel and starred in several TV movies.
In 1999, Melissa landed a small part in a movie named Can't Hardly Wait, and then starred in Drive Me Crazy, a movie that includes the number-one hit by Britney Spears on its soundtrack. She has appeared in other movies since Drive Me Crazy, but none have brought her as much recognition.
In 2003, Hart and her production company, Hartbreak Films, produced a miniseries documenting her wedding to musician Mark Wilkerson, a member of the band Course of Nature.