Lee is famous for, amongst others, playing the title role in Singapore's Mediacorp Channel 5 television sitcom Police & Thief as Lee Tok Kong, Phua Chu Kang Pte Ltd as guest appearance Lee Kok Peng from season 5 until season 7 and in Mediacorp Channel 8 long series television drama Holland V as Su Hao. He also gained recognition for his work with Jack Neo and Henry Thia in films such as Money No Enough and Liang Po Po: The Movie and long-running comedy variety programme Comedy Nite (搞笑行动). He made his directorial debut in the comedy horror film The Ghosts Must Be Crazy.

Along with long-time colleague Christopher Lee, Mark Lee was awarded the coveted All Time Favourite Artiste award in the Star Awards 2010 and became the first host-cum-comedian to win the award as the previous winners were predominantly thespians. As such he will no longer be in the run for the Top 10 Most Popular Male Artistes awards in future Star Awards.