Illinois State (1-0) racked up 656 total yards - the fifth most in school history - including 356 yards rushing and recorded its first shutout since beating Murray State 42-0 in 2005.
Patrick Ivy intercepted a pass from DraShane Glass on Mississippi Valley State's first possession, setting up the first of two rushing touchdowns by Redbirds quarterback Tre Roberson with 10:28 left in the first quarter.
Roberson completed 10 of 15 passes for 204 yards with two touchdowns and one interception. He added 41 yards rushing on seven carries.
James Graham finished with 115 yards rushing in his first collegiate action.
Four Mississippi Valley State players combined to go 6-of-15 passing for 36 yards and the Delta Devils (1-1) converted on 2 of 15 third downs.