"I realize this decision is surprising to many, but I know in my heart that it is the right decision and I look forward to spending more time with my family and pursuing other interests," Locker said in a statement.
Locker, 26, was the eighth overall pick in the 2011 draft out of the University of Washington, and the Titans had hoped the hard-working signal-caller would be a long-term answer for them.
But injuries and inconsistency prevented that from happening.
Locker played in just 30 of 64 possible games and missed time over the years due to a variety of injuries including a dislocated shoulder (2014), a Lisfranc injury (2013), a sprained MCL (2013) and a sprained hip (2013).
The Titans went with veteran Matt Hasselbeck in Locker's rookie year. After Locker took over as the starter in 2012, those injuries limited him to just 25 starts over three seasons.
A very fast quarterback, Locker was at his best on the move. But Ken Whisenhunt, who took over as Titans coach in 2014, prefers a pocket passer. Rookie Zach Mettenberger took over the starting role in Tennessee last season.
In the spring of 2014, the Titans declined to exercise a fifth-year option for more than $14 million for Locker in 2015.
"Football has always played a pivotal role in my life, and I love the game," Locker said, "but I no longer have the burning desire necessary to play the game for a living; to continue to do so would be unfair to the next organization with whom I would eventually sign."
Locker also was a former baseball star, and was selected in the 10th round of the MLB amateur draft in 2009 by the Los Angeles Angels.
Angels general manager Jerry Dipoto, though, said Tuesday he didn't see a fit.
"We're not interested in him as a baseball player," Dipoto said, according to MLB.com. "We're going to focus on the guys we have. We have enough going on."
ESPN.com Titans reporter Paul Kuharsky contributed to this report.