The 24-year-old put in a fantastic performance on the ground, as the Titans dominated the Jaguars, winning 30-9.
With the impressive run, Henry equalled Dallas Cowboys Hall of Fame running back Tony Dorsett for the longest run in NFL history, which was set in January 1983.
Henry ran for a franchise record 238 yards on the night, as the Titans kept their playoff hopes alive with the victory in Nashville.
He began the outstanding play by making a cut to the outside from the Titans one-yard line.
The running back, who weighs 17st, then brushed aside Jaguars linebacker Leon Jacobs with a stiff-arm, as he began to break away out of his own half.
Henry then used his strength again against Jags cornerback A.J. Bouye, who ended up being thrown to the ground, as Henry closed in on the end zone.
Before the play the Titans were 7-2 up and were looking to bounce back after conceding a bizarre safety, in which rookie Cameron Batson fumbled a punt return into his own end zone.
Henry’s 99-yard touchdown was his second trip to the end zone during the the game.
He went on to add two more rushing TDs in the third quarter, helping secure a comfortable victory over their AFC South rivals and take the Titans record to 7-6.
Before this break-out performance Henry’s longest run this season was only 16 yards and was averaging 3.7 yards per attempt.
Ahead of Thursday’s clash he was leading the Titans with 474 rushing yards from 128 carries for five touchdowns.
Henry also equalled the Titans franchise record with a career-high four touchdowns against the Jaguars with just 16 carries on the night.
Tennessee have now won six of their last seven against Jacksonville.
Next up for the Titans is a road trip to the big apple next Sunday to face the New York Giants.
The Jaguars, who are now 4-9, have had a disappointing campaign this season.
Their next game is at home against the Washington Redskins.