Vanderbilt running back Ralph Webb and wide receiver Kalija Lipscomb each had two touchdowns.
The Commodores' defense held a Blue Raiders' offense that averaged 517.7 yards a game last year to 215, and got in Middle Tennessee State quarterback Brent Stockstill's face all night.
Vanderbilt defensive end Dare Odeyingbo and linebacker Charles Wright each had two sacks.
Stockstill was just 18 of 31 for 166 yards, one touchdown and one interception.
Leading 21-0 at the break, the Commodores put the game out of reach early in the third quarter.
After the Blue Raiders went three-and-out, Shurmur hit Webb with a quick screen to the left sideline, and Webb easily raced 73 yards for a score.
Vanderbilt had taken command at the outset. The Commodores took the opening kickoff and drove 80 yards in five plays, with Shurmur finding Lipscomb in single coverage for a 37-yard score.
Vandy cornerback Bryce Lewis then picked off a Stockstill pass and returned it to the Middle Tennessee 40. A screen pass to Webb set up his 1-yard scoring run.
On the next drive, Shurmur found Lipscomb wide-open in one-on-one coverage in the left side of the end zone for the score.
Vanderbilt had 245 yards at half to the Blue Raiders' 72.
The Blue Raiders' lone score came when Stockstill hit wide receiver Richie James with a 22-yard touchdown pass with 11:54 left.
James, the NCAA's career leader in receiving yards among active players, had 10 catches for 112 yards, most of the yardage coming in the fourth quarter.