Jeremy Johnson hauled in a 19-yard touchdown 33, in the Battle for the Iron Skillet.
Casey Pachall's pass on 4th-and-2 on the ensuing TCU possession fell incomplete as SMU celebrated its first win over the Horned Frogs since 2005.
Darius Johnson had a fantastic day for SMU (4-1) as he caught 12 balls for 153 yards and two scores. Terrance Wilkerson had 97 yards and a score on three receptions, while Jeremy Johnson accumulated 69 yards on six catches for the Mustangs, who are off to their best start since 1986.
McDermott threw for 349 yards and four scores on 23-for-45 passing, while Zach Line led all rushers with 120 yards on 21 carries.
Pachall accounted for 304 yards and three touchdowns on 30-of-42 passing, Ed Wesley rushed for 93 yards on 11 carries and Josh Boyce had 94 yards and a score on seven receptions for TCU (3-2).
TCU came into the game with the third-longest home-winning steak in the country with 22 straight wins, behind Oklahoma (38) and Boise State (33). SMU lost four consecutive games against TCU, and 10 of the past 11 meetings coming in.