Frank DiLeo graduated from Central Catholic High School. DiLeo began his career in the music industry in the late 1960s, shortly after high school, as a rack jobber (distributing records to Retail stores) in Pittsburgh. Following a number of brief, higher-profile jobs, he was hired as a promotion staffer in Cleveland by CBS Records subsidiary Epic Records in 1968. He promoted albums by The Hollies, Donovan and Sly & the Family Stone to local radio stations, and was later promoted to the company's regional office in Chicago. Circa 1969 he was "headhunted" by RCA Records in New York City, followed by a stint at Bell Records. After a year with Bell he "retired" from the music Business and moved back to Pittsburgh. His return to the music industry was prompted by an "electrical fire" which destroyed his Pittsburgh home, for which his insurance carrier reportedly refused to pay out.

In 1979, CBS Records President Walter Yetnikoff hired his old friend DiLeo to work for Epic Records in New York City as Vice President of National Promotion. Overseeing a staff of 65 people and a multimillion-dollar budget, Frank helped guide Epic Records from a small $65 million company to a $250 million powerhouse; during this period Epic outperformed its sister label Columbia Records for two years running. Artists signed to Epic included Quiet Riot, REO Speedwagon, Ozzy Osbourne, Gloria Estefan, Luther Vandross, Meat Loaf, Cyndi Lauper, Culture Club and Michael Jackson, among others. He was voted executive of the year for Epic Records, received over 80 gold and platinum awards, and was credited for taking Epic Records from the number fourteen label in the U.S. market to number two. In 1984, after the record-setting success of his Thriller album, Michael Jackson asked DiLeo to take over as his manager. DiLeo was the executive Producer for the full-length movie Moonwalker, wrote and executive produced three Pepsi-Cola commercials (including negotiating a landmark endorsement deal), and eight music videos including the Grammy winning video "Leave Me Alone". DiLeo managed Jackson's Bad World Tour, and the Jackson family's Victory Tour. DiLeo managed Jackson until February 14, 1989 when Jackson accused DiLeo of tampering with money, DiLeo later partnered up with Jackson again in 2009 for Jackson's This Is It. The Last Time DiLeo saw Jackson was at the Ronald Reagan UCLA Medical Center on June 25, 2009 DiLeo told David Gest "I got to spend a few moments alone with him, I told him what I thought, before kissing him on the head and saying my last goodbye".

In 1991 Youngstown,Ohio Mob Boss Joseph "Little Joey" Naples was killed outside a home he was having built in Beaver Township, Mahoning County. He was driving DiLeo's Ford Mustang Convertible. Naples was a Pittsburgh member of the Genovese Crime Family, Lamica was known to have the same mutual family ties. In 2011 DiLeo suffered a heart attack and was treated at Cedars Sinai Medical Center in Los Angeles.

In 2009, The Wall Street Journal reported that DiLeo was once again managing Michael Jackson's career.

Frank DiLeo died on August 24, 2011, in a care facility outside Youngstown, Ohio, after experiencing complications following heart surgery. He was 63 years old.