Manson "died of natural causes at 3am Monday at a hospital in Kern County, the California Department of Corrections and Rehabilitation said in a brief statement.
Debra Tate -- the sister of Manson's most famous victim, Sharon Tate -- told celebrity website TMZ that she received a call from prison officials notifying her of Manson's death.
Manson was earlier moved from the Corcoran State Prison to a hospital in the city of Bakersfield, in Kern County, to be treated for an unspecified illness, US media reported.
In the late 1960s, Manson headed an apocalyptic cult that committed random murders in upscale mostly white neighborhoods of Los Angeles -- unleashing a wave of panic in the city and beyond.
The aim was for African Americans to be blamed, in the hope of sparking what he believed to be an impending and apocalyptic race war.
His "Family" disciples committed at least nine murders, but it was the horrific killing spree of seven people on August 9-10, 1969 that sealed his notoriety -- and earned him life in prison.
The famous victim was 26-year-old movie actress Sharon Tate, the heavily-pregnant wife of director Roman Polanski, who pleaded for the life of her unborn child before she was stabbed to death.
Manson was not present, but ordered the killings.
Manson, who has never shown remorse, was sentenced to death in 1971 along with four of his disciples for having led the killings of seven people.
The sentences were later commuted to life in prison when California abolished the death penalty.
During his marathon trial, Manson -- with a beard, long unwashed hair, and a swastika tattooed on his forehead -- was portrayed as a drug-crazed loner with mesmerizing powers of persuasion.
Upon his death, he had been in prison in California since 1971, during which he applied for parole 12 times, telling the court on the last occasion in 2012 that he was "a very dangerous man."
In each case, he was denied release and was not eligible to apply again until 2027.
In a 1981 interview conducted from jail, Manson said he had already spent most of his life in prison and felt at home there.