Chad Steele, a spokesman for the Baltimore Ravens, said Thursday that Mackey's wife, Sylvia, notified the team about her husband's death. No official cause was given.
Mackey played for the Baltimore Colts from 1963 to 1971. He also played for the San Diego Chargers in 1972. He caught 331 passes for 5,236 yards and 38 touchdowns in a 10-season career.
An NFL labor agreement ratified in 2006 includes the so-called "88 Plan," named for Mackey's number, 88. It provides up to $88,000 per year for nursing care or day care for ex-players with dementia or Alzheimer's disease, or $50,000 for home care.
"John Mackey is still our leader. As the president of the NFLPA, he led the fight for fairness with a brilliance and with ferocious drive," current NFLPA executive director DeMaurice Smith said in a statement. "His passion continues to define our organization and inspire our players. His unwavering loyalty to our mission and his exemplary courage will never be forgotten."
The health care of former players has become a prominent issue in the negotiations for a new collective bargaining agreement. An NFL lockout has been ongoing since March 12.
"John Mackey was one of the great leaders in NFL history, on and off the field," NFL Commissioner Roger Goodell said in a statement. "He was a Hall of Fame player who redefined the tight end position. He was a courageous advocate for his fellow NFL players as head of the NFL Players Association. He worked closely with our office on many issues through the years, including serving as the first president of the NFL Youth Football Fund. He never stopped fighting the good fight."
Mackey was drafted in 1963 out of Syracuse -- by the NFL's Colts in the second round and the AFL's New York Jets in the fifth round.
Mackey wound up playing for the Colts just as the passing game was taking on a major role in professional football. His size, speed and ability to catch the ball while also blocking in the running game made him the prototype for future generations of tight ends.
Mackey caught 35 passes for 726 yards as a rookie in 1963, when he was selected to the first of five Pro Bowls. He also was voted first-team All-Pro by The Associated Press in 1966, '67 and '68.
Mackey helped the Colts beat the Dallas Cowboys in Super Bowl V, catching a Johnny Unitas pass that had been deflected off two other players for a 75-yard touchdown. Baltimore won the game 16-13 on Jim O'Brien's 32-yard field goal in the closing seconds.
After he retired, Mackey joined Mike Ditka as the first tight ends selected to the Pro Football Hall of Fame. The John Mackey Award was established to honor the nation's top college football tight end, and Syracuse retired his number in 2007.
Mackey has become closely associated with the plight of many former players who helped build the NFL in the era before million-dollar contracts, safer equipment and better health care.
In later years, Mackey suffered from frontotemporal dementia that's believed to have been caused by the contact associated with playing football. Four years ago, the dementia forced Mackey into living in an assisted-living facility.
The costs associated with his care, which far outpaced Mackey's pension, led to the "88 Plan" for retired players. Now, former players are pushing for better pension plans and health benefits from the league.
"John Mackey has inspired me and will continue to inspire our players," Smith posted on Twitter. "He will be missed but never forgotten."