The 33-year-old World Cup winner, who won 55 England caps, will retire at the end of Harlequins' National League One campaign.
Greenwood made three Lions tours and was a crucial member of England's 2003 World Cup win when he finished joint-top tryscorer for the tournament with five.
Greenwood told the Daily Telegraph: "As hard as it has been for me to admit, the time has come to retire from the game that has always been part of my life.
"I understand the reasons. I'm getting slower - if that was possible. I can no longer perform to the levels I wish, and my body is falling apart; six operations, broken bones, a near-death experience, torn ligaments, dislocated shoulders and hamstrings tighter than guitar strings."
Greenwood's top-flight playing career began with Leicester before he moved to Harlequins in 2000.
The son of former England flanker and coach Dick Greenwood, he toured South Africa in 1997 and Australia four years later with the Lions but did not play a Test.
Injuries ruined those two trips for him, most famously in South Africa when he swallowed his tongue after a head collision, but he played two Lions Tests in New Zealand last year.
Greenwood added: "For a Blackburn lad who was only ever after a run-around with the lads, rugby has taken me on one hell of a journey.
"Memories both good and bad, like Durban after winning the Lions series in 1997, and Auckland when we had lost a series 3-0.
"In Sydney on that famous night, but also in Paris in 1999 when our World Cup fell apart.
"It won't be easy, and I'd be lying if I said I wasn't nervous. My life in rugby has been great."