After scoring two straight touchdowns to end the second quarter, SMU forced a fumble on the opening kickoff of the third quarter and recovered it for a touchdown to extend its halftime lead to 35-14 in the opening seconds of the second half.
Houston starting quarterback David Piland did not play in the third quarter as he left the game after SMU's Taylor Reed intercepted him for a six-yard defensive score to put Mustangs up 28-14 at halftime.
Piland passed for 181 yards on 15-of-25 passing in the first half with two interceptions before leaving the game.
Bram Kohlausen opened the third quarter for Houston and went 2-for-7 for 13 yards and two interceptions, including one to SMU's Darrien Wright who returned it 10 yards for the Mustangs' second defensive touchdown of the game to extend their lead to 45-14.
Kohlausen was replaced in the the game by Crawford Jones who led Houston to 14 answered points on touchdown passes to Charles Sims and Daniel Spencer to cut SMU's lead to 45-28 with 5:04 left in the third quarter.
The Mustangs scored the final 14 points of the fourth quarter on Garrett Gilbert's third and fourth touchdown passes of the game to extend their lead to 59-28 after three quarters.
Houston has turned the ball over eight times through three quarters.