Epstein, 66, was found unresponsive in his cell at about 6:30 am (1030 GMT).
Metropolitan Correctional Center said that efforts to save him were initiated by prison staff and emergency medical services but he was pronounced dead at hospital, the prison’s statement said.
According to U.S. media reports, which cited officials familiar with the matter, the multimillionaire financier hanged himself.
The prison did not confirm the suicide but said the FBI was investigating the incident.
U.S. Attorney General William Barr in a statement said he was “appalled” to learn of Epstein’s death while in federal custody and that the incident raises serious questions.
“In addition to the FBI’s investigation, I have consulted with the Inspector General who is opening an investigation into the circumstances of Mr. Epstein’s death,” Barr said.
The U.S. attorney in Manhattan said its investigation would continue, noting that Epstein’s indictment included charges that he conspired with other people in the commission of the alleged crimes.
U.S. Attorney Geoffrey Berman also encouraged anyone feeling they might have been victim to come forward.
He praised those who already have.
“To those brave young women who have already come forward and to the many others who have yet to do so, let me reiterate that we remain committed to standing for you,” Berman’s statement said.
Epstein, who had ties to numerous wealthy Americans, including U.S. President Donald Trump and former president Bill Clinton, had reportedly been placed on suicide watch after a separate attempt made while in custody toward the end of last month.
It remained unclear whether he was on suicide watch at the time of his death, though some U.S. media including the New York Times reported the watch had been removed a few days ago.
Epstein was indicted last month on charges of sex trafficking of minors and conspiracy.
He had pleaded not guilty and was denied bail three weeks ago.
His death followed the publication on Friday of a cache of documents that provided more extensive details on how the alleged sex trafficking network operated between 2002 and 2005.
The new information included descriptions of how he allegedly ordered an associate to lure girls as young as 14 to his homes in New York and Palm Beach, Florida, coerced them into sex and then used them to draw in other victims.
Epstein had faced sex crime charges in 2008 in Florida related to the alleged network but made a deal with prosecutors that resulted in a relatively light prison sentence.
Critics said the punishment was too lenient and victims’ advocates said it was done without the knowledge of the girls involved.
Alex Acosta, a federal prosecutor in Florida at the time of the earlier plea deal, was forced to resign as Trump’s secretary of labour last month.
The more recent charges were contained in a federal indictment filed in New York.
Epstein was arrested on July 6 and entered a not guilty plea but a judge ordered him detained after prosecutors argued that Epstein was a flight risk due to his vast wealth and resources.
Lisa Bloom, a lawyer representing some of the women, said Epstein’s apparent suicide indicated that he knew he was guilty and that his wealth would not prevent a conviction.
“He knew justice was coming and he could not face it,” Bloom tweeted.
She also said civil cases against his estate would proceed.