The 79-year-old died at Ashworth Hospital, a secure psychiatric unit in Merseyside where he had been detained since 1985.
Brady, who was jailed in 1966, buried four of his victims in graves on Saddleworth Moor, Greater Manchester.
One victim's brother said Brady's death would not end their "nightmare".
A Mersey Care NHS Foundation Trust spokesman said Brady had died at 18:03 BST on Monday.
Brady, who was born in Glasgow but later moved to Manchester, was jailed at Chester Assizes 51 years ago for the murders of John Kilbride, aged 12, Lesley Ann Downey, 10, and Edward Evans, 17.
In 1985 he also admitted to the murders of Pauline Reade, 16, and Keith Bennett, who was 12.
The children had been abducted by Brady and his lover Hindley, who died in prison in 2002, between 1963 and 1965.
Brady never revealed where Keith's remains were buried. The boy's mother Winnie Johnson, who died in 2012, had repeatedly pleaded for Brady to do so.
Brady and Hindley were caught when her brother-in-law David Smith, who was a petty criminal, phoned the police after seeing Brady abuse and strangle Edward Evans.
The officers caught Brady and Hindley at home, retrieving Edward's body from the bedroom, along with Brady's library of volumes on perversion and sadism.
Martin Bottomley, the head of Greater Manchester Police's cold case unit, said the force would never give up the search for Keith and Brady's death did "not change that".
He said: "Our aim, as it always has been, is to find where Keith is buried and give closure to his surviving family members so they can give Keith the proper burial they so desperately want.
"Whilst we are not actively searching Saddleworth Moor, we will act on credible and actionable information that will help lead us to him."
Brady's lawyer Robin Makin told BBC Radio 4's Today programme he was with his client in hospital less than two hours before his death.
"I got a call that he wanted to see me - he was obviously well aware that his death was imminent," he said.
He described the encounter as "quite a moving sort of situation", where the pair discussed Brady's legal affairs and funeral arrangements.
He said the whereabouts of the remains of Keith Bennett did not come up in conversation.
"I would be very surprised if he really had information that was useful.
"He did go to the Moors a long time ago and I suspect that if there had been information for him that he could have provided, he would have provided it then."
Describing coverage of the search for Keith's body as a "frenzy", he said: "I would very much hope that the remains can be found, but unfortunately I haven't got any information that's going to assist."
Keith's brother Alan runs a website, Searching for Keith, in an ongoing attempt to locate his body.
John Kilbride's brother, Terry, told the Sun newspaper: "It's been years and years of anguish and pain for us and the families of the victims.
"He's dead but we will have to still live with the nightmare that he left behind."
Speaking about the case of victim Lesley Ann Downey, former police officer Norman Brennan told of the "grief and torment" he had seen on the faces of her mother and father.
Police found photographs of the naked 10-year-old, along with tape recordings of her final moments pleading for her life as she was brutally abused.
Mr Brennan told BBC Two's Newsnight: "To know that your daughter was lost, alone and murdered and then actually her death was recorded, the grief can never ever be etched from your mind.
"Those two individuals, Myra Hindley and Ian Brady, they didn't just destroy five young children's lives.
"The... false hopes that they gave the families for over 50 years destroyed all of the families as well, even to this day."
Brady had been on successive hunger strikes since 1999, arguing he should be allowed to die, but had been force-fed because he was considered mentally ill.
He campaigned for several years to be moved from Ashworth to a Scottish prison where he would not be force-fed and would be allowed to die if he wished.
The Mersey Care Trust was unable to confirm the cause of Brady's death, but said he had been given oxygen for a while.
Brady was not found dead in his room, its spokesman said, but he was unable to confirm if anyone was with him when he died, adding: "Quite possibly. I don't know."
Moors Murderer Ian Brady, who tortured and killed five children with Myra Hindley in crimes that shocked the nation, has died.