The soon-to-be 40-year-old announced his decision to retire on Instagram with a post that has a photo collage of his two children and includes the hashtag #2ndAndFinalRetirement.
Harrison played almost his entire career with the Steelers, collecting 80.5 of his 84.5 career sacks while wearing black and gold, a franchise record.
Despite an illustrious career with the revered Pittsburgh Steelers, Harrison and the team parted on negative terms.
Harrison has previously retired in 2014, but returned to the Steelers by Week 4 of that season.
Harrison, 39, played a total of 15 seasons in the league, spending 13 years with the Steelers during two spells.
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.
Harrison was named Defensive Player of the Year for the 2008 season, which he capped with the longest interception return in Super Bowl history, his 100-yard effort helping the Steelers to victory over the Arizona Cardinals in Super Bowl XLIII.
Harrison played just five games for the Steelers during the 2017 season and was released by the franchise in December. He made the Pro Bowl five times and was named an All-Pro twice during his 15-year National Football League tenure.