Detmer redshirted for the Cougars during the 1987 season, and shared quarterback duties with Sean Covey as a freshman in 1988. Detmer started a game against New Mexico, and passed for 333 yards and 5 touchdowns in a 65-0 BYU victory. He was named Most Valuable Player of the 1988 Freedom Bowl, leading BYU to a come-from-behind 20-17 victory over Colorado.
Detmer became a full-time starter in 1989. He emerged as one of the top quarterbacks in the nation, passing for 4,560 yards and 32 touchdowns during the regular season. His passer rating of 175.6 led the NCAA, and he finished second to Houston's Andre Ware in total offense. He led BYU to a WAC Championship, the team's first since 1985. Detmer finished the season with a strong performance against Penn State in the 1989 Holiday Bowl, setting NCAA records for most passing yards (576) and most yards of total offense (594) in a single bowl game.
During Detmer's junior season (1990) he passed for 5,188 yards and 41 touchdowns in 12 regular season games, finished the year with 42 NCAA records, and tied for five others. BYU achieved an 28-21 upset victory over top-ranked Miami; he led the Cougars by passing for 406 yards and 3 touchdowns against the defending national champions. Detmer was awarded the Heisman Trophy, and received many other honors (including the Maxwell Award and the Davey O'Brien Award). He was named consensus All-America by the Associated Press, UPI, Newspaper Enterprise Association, Football Writers, Walter Camp, Football News, Scripps Howard, and the Sporting News. Unfortunately for Detmer and BYU, the season ended in disastrous fashion: The Cougars lost 59-28 in their final regular season game (against Hawaii), then lost 65-14 to Texas A&M in the 1990 Holiday Bowl. Detmer was knocked out of the game against Texas A&M, suffering two separated shoulders that required off-season surgery.
The 1991 season, Detmer totaled 4,031 passing yards and 35 touchdowns in regular season play during his senior year. He finished third in the Heisman Trophy voting, but won the Davey O'Brien Award again and also earned the Sammy Baugh Trophy and Today's Top VI Award. Additionally, he was named a consensus All-American.
Detmer finished college with the following career totals: 1,530 pass attempts; 958 completions; 15,031 passing yards; 121 touchdown passes; 14,665 yards of total offense; 135 touchdowns responsible for; and 162.7 passer rating - all were NCAA records at the time. In all, he finished his college career with 59 NCAA records and tied for three others. Including statistics from bowl games, Detmer totaled 16,206 passing yards and 127 touchdown passes at BYU.