Samuel Little, 80, had diabetes, heart problems and other ailments, he died in a California hospital.
He was serving a life sentence on multiple murder charges.
California Department of Corrections spokeswoman Vicky Waters said there were no signs of foul play and that a coroner will determine the cause of her death.
A career criminal who had been in and out of jail for decades, Little denied for years that he had ever killed anyone.
Then, in 2018, he opened up with Texas Ranger James Holland, who had been asked to question him about a murder that Little turned out not to commit.
However, during approximately 700 hours of interviews, Little provided details of dozens of murders that only the killer would know.
At the time of his death, Little had confessed to killing 93 people between 1970 and 2005.
Most of the murders took place in Florida and Southern California.
Authorities, who are continuing to investigate his claims, said they have confirmed nearly 60 killings and have no reason to doubt the others.
“Nothing he has ever said has ever been proven to be wrong or false,” Holland told CBS 60 Minutes news magazine in 2019.
The numbers dwarf those of Green River killer Gary Ridgeway (49), John Gacy (33) and Ted Bundy (36).
Almost all of Little’s victims were women, many of them prostitutes, drug addicts or poor people living on the fringes of society.
They were individuals, he said he believed they would leave few people behind to search for them and little evidence for police to follow.
In fact, local authorities in states across the country initially classified many of the deaths as accidents, drug overdoses, or the result of unknown causes.
Little strangled most of his victims, usually shortly after meeting them during casual encounters.
He drowned one, a woman he met at a nightclub in 1982.
Once a strong and robust boxer who used his powerful hands to strangle his victims, now he used a wheelchair to get around.
Holland has described Little as a genius and a sociopath, adding that the killer was never able to adequately explain to him why he did what he did.
Although known as an expert interrogator, Holland himself said he could only guess why Little opened up to him.
The ranger worked tirelessly to create and maintain a bond with the killer during their hundreds of hours of interviews, bringing him favorite snacks like pizza, Dr. Pepper, and grits, and discussing their mutual interest in sports.
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He also assured Little that he would not be executed.
Mr. Holland addressed Little by his childhood nickname, Sammy, while Little called Mr. Holland Jimmy and once told the Los Angeles Times that he had “found a friend in a Texas ranger.”
He told 60 Minutes that he hoped his confessions could exonerate anyone wrongly convicted of their crimes.
“I say if I can help get someone out of jail, you know, then God could smile a little more at me,” he said.
A bystander who traveled the country when not in jail for theft, assault, drugs or other crimes, Little said he began killing in Miami on New Year’s Eve 1970.
“It was like drugs,” he told Holland.
His last murder was in 2005, he said, in Tupelo, Mississippi.
It also killed people in Tennessee, Texas, Ohio, Kentucky, Nevada, Arkansas, and other states.
Kentucky authorities finally caught up with him in 2012 after he was arrested on drug charges and his DNA linked him to three murders in California.
When he began recounting the other murders, the authorities were amazed at how much he remembered.
His paintings, they said, indicated that he had a photographic memory.
A murder was solved after Little recalled that the victim was wearing false teeth.
Another after he told Holland he had killed the victim near an unusual-looking set of bows in Florida.
A victim he met outside of a Miami strip club in 1984 was remembered as a 25-year-old with short blonde hair, blue eyes and a “hippie look.”
As he continued to speak, authorities across the country rushed to investigate old cases, locate relatives, and end the families.
Little revealed few details about his own life, other than that he was raised in Lorain, Ohio, by his grandmother.
Authorities said his name was often Samuel McDowell.
He was married once, Little said, and was involved in two long-term relationships.
He claimed that he developed a fetish for women’s neck after becoming sexually aroused when he saw his kindergarten teacher touch his neck.
He was always careful, he added, to avoid looking at the neck of his wife or girlfriends and never hurting anyone he loved.
“I don’t think there is another person who did what I liked to do,” he told 60 Minutes.
“I think I am the only one in the world. And that is not an honor, it is a curse. “