Mae, the first surrogate mother otter to raise a pup on exhibit at the aquarium, began having seizures last Wednesday and died late Saturday afternoon, aquarium spokesman Ken Peterson said.
The animal's cause of death is unknown, pending the results of a necropsy.
Mae, nicknamed "Mayhem" by aquarium staff because of her feisty personality, was rescued in April 2001 as a two-day-old pup and ended up staying at the aquarium after researchers determined she was not acquiring the skills needed to survive in the wild.
The name Mae -- that of a truck stop waitress with a screeching voice in Monterey-area native John Steinbeck's famous book "The Grapes of Wrath" -- was chosen by the public for the animal in an online poll.
Mae's first surrogate pup, Kit, is now at SeaWorld in San Diego, and she also served as a surrogate mother to four other pups and as a companion animal to many others at the aquarium.
Peterson said sea otters typically live up to 20 years old.
The sea otter exhibit at the aquarium is currently closed for renovations and is set to reopen in mid-March 2013.