Dennis Sheehan, 68, was found dead in his room at the Sunset Marquis Hotel after deputies responded to reports of a person not breathing, officials said.
"We've lost a family member, we're still taking it in," singer Bono said in a statement on the band's website. "He wasn't just a legend in the music business, he was a legend in our band. He is irreplaceable."
Craig Harvey, a spokesman for the Los Angeles County coroner's office, said Sheehan possibly died of natural causes.
Los Angeles County firefighters were dispatched to the hotel at 5:34 a.m. after a report of a person in cardiac arrest, said fire Inspector Randall Wright.
Firerfighters arrived six minutes later, but did not transport anyone to the hospital. They left about 5:59 a.m. and the sheriff's department took over the investigation, Wright said.
Homicide investigators are looking into his death, said Sgt. Kevin Rasmussen of the Los Angeles County Sheriff's Department.
Sheehan had been associated with the band for more than 30 years, starting in 1982.
He had organized the band's tours and helped with solo projects, including arranging Bono's appearance before Congress where he testified in support of more aid to Africa.
Sheehan's music career extended beyond U2 and he worked on tours with Led Zeppelin, Lou Reed, Patti Smith, The Damned, Siouxsie and the Banshees and Soft Cell.
In 2008, he received the Parnelli Lifetime Achievement Award in recognition of his more than four decades in the live music industry.
"With profound sadness we confirm that Dennis Sheehan, U2's longstanding tour manager and dear friend to us all, has passed away overnight," Live Nation promoter Arthur Fogel said in the U2 statement. "Our heartfelt sympathy is with his wonderful family."