The family moved south to Fort Lauderdale, Florida, when Piccolo was three, due to his parents' concerns for his brother Don's health.

Piccolo and his brothers were athletes, and he was a star running back on his high school football team, although he considered baseball his primary sport.

He led the nation in rushing and scoring during his senior season in 1964,[3] and was named the Atlantic Coast Conference (ACC) Player of the Year,[4] yet went unselected in both the AFL and NFL drafts.

[5][6] In the balloting for the Heisman Trophy won by John Huarte of Notre Dame, Piccolo was tenth, just ahead of Joe Namath of Alabama, and future teammate Gale Sayers of Kansas.

[17][18][19] The next week in Atlanta, he scored a fourth-quarter touchdown on a one-yard run,[20][21] and then voluntarily removed himself from the game, something he had never done,[22] raising great concern among his teammates and coaches.

Breathing while playing had become extremely difficult for him, so when the team returned to Chicago, he was promptly sent for a medical examination at which he was diagnosed with embryonal cell carcinoma.

Bothered by continuing chest pain afterward, he was re-admitted to the hospital in early June where doctors determined the cancer had spread to other organs, particularly his liver.

Dick Butkus, Randy Jackson, Ralph Kurek, Ed O'Bradovich, Mike Pyle, and Gale Sayers were the six Bears teammates who served as pallbearers at Piccolo's funeral at Christ the King Catholic Church in Chicago on June 19.

[32] It first aired Tuesday, November 30, 1971, on ABC, less than 18 months after his death, and starred James Caan as Piccolo and Billy Dee Williams as Sayers.