Nam Sang-mi began her acting career in the 2003 MBC melodrama Love Letter. In 2005, she landed her first leading role in the MBC series Sweet Spy, which won her Best New Actress at the MBC Drama Awards. She was also nominated for Best New Actress for TV at the 42nd Baeksang Arts Awards for her work in the series. In 2007, she starred in the MBC drama Time of Dog and Wolf with Lee Jun-ki and Jung Kyung-ho. The series earned her an Excellence Award at the MBC Drama Awards. In 2012, she appeared in the top-rating MBC drama Light and Shadow, which scored her a Top Excellence Award nomination at the MBC Drama Awards. In 2013, she bagged a Top Excellence Award at the SBS Drama Awards for her portrayal of a radio writer caught in a love triangle between two men in Goddess of Marriage. In 2014, she reunited with Lee Jun-ki in the KBS2 sageuk Joseon Gunman, in which she took home an Excellence Award at the KBS Drama Awards.

Nam Sang-mi and her businessman boyfriend tied the knot on January 24, 2015. They welcomed their daughter on November 12, 2015.