The sheriff's office says Afeni Shakur Davis, 69, had passed via their Twitter account.
Sheriff's office deputies responded to Davis' home in Sausalito on reports of a possible cardiac arrest.
They say she was transported to a hospital where she died at 10:28 p.m.
Born Alice Faye Williams, Shakur changed her name as an adult when she became a political activist and joined the Black Panther movement. She was pregnant with Tupac in 1971 and incarcerated while she and other Panthers faced conspiracy charges that were later dismissed.
Shakur was an inspiration for her son's music and oversaw his music catalog and legacy after his death.
Tupac Shakur died in 1996 at age 25, the victim of a drive-by shooting as he was leaving a boxing event in Las Vegas. The murder remains unsolved.
The sheriff's office will lead an investigation to determine the exact cause and manner of Davis' death.
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