The US actor and comedian had been admitted to hospital in Chicago, Illinois, last week to receive treatment for pneumonia.
In a statement, his publicist Danica Smith said: "Bernie Mac passed away this morning from complications due to pneumonia in a Chicago area hospital."
She added that no other details were available and requested privacy for his family.
Mac started his stand-up comedy career at an early age, but is also well known for his successful acting career. He appeared in high-profile movies such as Ocean's Eleven, Charlie's Angels sequel Full Throttle and Transformers, as well as his own Fox sitcom The Bernie Mac Show, for which he received two Emmy nominations.
He once revealed that he suffered from the lung disease sarcoidosis, but it was believed to have gone into remission in 2005. After he checked into hospital last week, his spokeswoman insisted that the pneumonia diagnosis was not related to the disease.