Lee Mi-sook began her career as an actress in the 1979 movie Thoughtless Mo-mo and became one of the most popular stars in the 1980s. In 1981, she took home the Best New Actress trophy at the 17th Baeksang arts Awards for her work in the film Flame Bird. In 1982, she starred in the MBC series Jang Hui-bin, which scored her the Daesang at the MBC Drama Awards. In 1984, she appeared in director Bae Chang-ho’s film That Year the Winter Was Warm, which earned her several Best Actress trophies. She then took home more Best Actress citations for her performance in the erotic drama film Mulberry in 1986 and Love Triangle in 1987. The latter served as her final movie before retiring from cinema after getting married. In 1993, she was awarded another Daesang at the SBS Drama Awards for the series How’s Your Husband. In 1998, she made her big screen comeback with the box-office hit An Affair, which is about a woman who falls in love with her sister’s fiancé. Her work in the movie won her Best Actress at the 19th Korea Association of Film Critics Awards and the 7th Chunsa Film Art Awards. In 2003, she bagged another Best Actress trophy at the 23rd Korea Association of Film Critics Awards for Untold Scandal. In 2008 and 2017, she received Top Excellence Awards at the MBC Drama Awards for East of Eden and Money Flower, respectively.

Lee Mi-sook and her plastic surgeon husband divorced in 2007 after being together for 20 years. They have a son and a daughter. In 2019, she expressed her willingness to testify to unearth the truth behind the death of actress Jang Ja-yeon, who committed suicide in 2009. She and Jang Ja-yeon were both under the management of The Contents Media agency.