"I've missed way too much for way too long...and I'm done".
He added the hashtag #2ndAndFinalRetirment to the post in reference to his brief retirement in August 2014 before returning to the Steelers the following month.
The Kent State product went undrafted in 2002, with most teams believing he was too small to be a pass rusher.
He then spent some time with the Baltimore Ravens and the NFL Europe's Rhein Fire before ending up back with the Steelers in 2004.
Known for delivering hard hits, Harrison began his National Football League career with Pittsburgh in 2002 and helped the Steelers capture the Super Bowl in 2006 and again in 2009.
Be sure to do an extra bench press and set of leg squats for James Harrison on Monday.
Harrison had previously said that he wanted to play another season or two.
He eventually became an NFL Defensive Player of the Year, five-time Bowler and two-time first-team All-Pro in Pittsburgh.
He was denied a third as the Steelers lost to the Green Bay Packers in Super Bowl XLV and, after being released by Pittsburgh last December, helped the New England Patriots to Super Bowl LII only to lose 41-33 to the Philadelphia Eagles in his last professional game.