The Hilltoppers (0-4, 0-1 Sun Belt Conference) extended a nation-leading 18-game home losing streak that dates back to September 2008.
The Red Wolves (3-2, 1-0) turned Western Kentucky over on downs with 3 minutes left in the fourth quarter and put together a nine-play, 67-yard drive to cap the win.
Bobby Rainey threw for a touchdown and received another to lead Western Kentucky. He also rushed for 86 yards.
Arkansas State, which avenged a 36-35 loss to the Hilltoppers last season, came into the game leading the Sun Belt in rushing but finished with a combined 25 yards on 28 attempts.