Stewart was blocking on a 26-yard run by Chris Johnson when Texans linebacker Barrett Ruud rolled onto his right leg. Trainers put an air cast on Stewart's lower right leg, while a cart quickly came out to pick him up.
He was taken into the locker room for observation, and officials later announced Stewart had a broken leg. Mike Otto replaced Stewart.
The right tackle had started 103 games since being drafted in 2005.
The Titans had a second offensive lineman hurt in the first half when left guard Steve Hutchinson injured his right knee. He returned briefly in the third quarter when left tackle Michael Roos got hurt and limped off the field before returning on the next series. Titans receiver Damian Williams hurt a hamstring missing a pass as he went out of bounds and collided with a security guard. He limped to the locker room and will not return.
Houston cornerback Brice McCain, starting with Johnathan Joseph out, hurt his left foot in the first half. Officials said in the third quarter he will not return. Tight end Garrett Graham suffered a head injury and also is out.