The Bulldogs scored 28 points and piled up a staggering 303 yards of offense in the first quarter alone.
After taking a 35-0 lead early in the second quarter, Sikeston's backup players were already in the game.
The Bulldogs totaled 560 yards of offense. Running back Darryl Howard had 110 yards on three carries with a touchdown in the first quarter.
Quarterback Trey Lewis rushed for 94 yards on three carries with a pair of TD runs, while also throwing for 82 yards, all in the first quarter. Lewis also intercepted a pass.
Janeil Hatchett had two receptions for 104 yards, including a 61-yard TD.
Sikeston's defense forced three turnovers and limited Perryville to 35 yards rushing and 120 total yards.
The Pirates fall to 0-8 on the season.
The Bulldogs (8-0) receive 13 points in the Class 4, District 1 standings to hold a one-point lead after Cape Central's 40-28 road victory over Farmington.
Sikeston will play at Houck Stadium on Thursday night to take on the Tigers, also 8-0, in a Class 4 showdown of state-ranked teams.