Now unbeaten through seven weeks, the Griffs are off to their best start in program history.
Western started fast jumping out to a 14-0 lead, but Southern outscored them 21-3 the rest of the first half to take a four point lead.
But they wouldn't find the end zone again.
The Lions six possessions in the second half resulted in two lost fumbles, threw two interceptions and two punts.
Travis Partridge hit Stephon Weaver on a six-yard touchdown pass to take a 28-21 lead, then hit the big play to seal the game.
After Southern fumbled the ball away on the Western one-yard line, Partridge hit Josh Walker for a record-setting 99-yard touchdown pass putting the Griffons on top 35-21. The reception is the longest in Missouri Western history.
Partridge finished the night 15-28 for 244 yards and three touchdowns. Walker led the team with 144 receiving yards on two catches.
Raphael Spencer led the Griffs with 77 yards on 20 carries, including a first half touchdown.