The No. 12 Griffons (7-2) lost to the No. 14 Hornets (9-0) for the first time since 2004, and have dropped back to back home games for the first time since 2008.
Emporia State jumped on top in the second quarter on a 13-yard touchdown pass from Brent Wilson and a pair of running scores by Dozie Iwuagwa.
Missouri Western trailed 21-0 before waking up. Travis Partridge ended a 11-play 86 yard drive with a touchdown pass to Alex Ferbet.
The Griffs added a John Schmiemeier field goal on the final play of the first half to cut the deficit to 11 points.
Western continued to push, reeling off 24 unanswered points to take the lead in the fourth quarter, but Emporia State opened up another two possession lead on a pair of one-yard touchdown passes from Wilson.
The Griffons cut into the lead with a two-yard touchdown run from Partridge, and got the ball back on an interception by Mike Jordan with 2:05 left in the game.
Western drove to the Emporia six-yard line with 16 seconds to play, but Partridge threw an interception to Gary Fortune on the goal line to end the threat.
Missouri Western's senior quarterback finished the game 22-39 for 298 yards, two touchdowns and four interceptions; he also gained 130 yards and two scores on the ground.
Sophomore receiver Stephon Weaver had a career day catching 10 passes for 163 yards and a touchdown.
The Griffons are back on the road next week against No. 8 Washburn.