Casey Clausen completed 24 of 29 passes for 263 yards with a touchdown and an interception while Cedric Houston rushed for 74 yards and a score on 13 carries.
Tennessee (2-0), which faces Florida in two weeks, opened a 17-0 lead at the intermission, then relied on its defense in the second half.
The Volunteers allowed only a 45-yard field goal to Brian Kelly 41 seconds into the final quarter.
The Blue Raiders (0-2) stayed close, but could not mount much of an attack against the Volunteers' defense, which accounted for the final nine points of the game.
Defensive back Jabari Greer blocked a punt out of the end zone for a safety that made it 19-3 with 9:19 remaining.
On Middle Tennessee's next possession, quarterback Andrico Hines fumbled and linebacker Kevin Simon recovered in the end zone for a touchdown with 5:27 left.
Hines completed 13 of 23 passes for just 109 yards and also was the leading rusher for the Blue Raiders with 63 yards on 19 carries.