In 2005 Bush was a unanimous First-team All-American and winner of the Heisman Trophy. He was also named the Associated Press College Football Player of the Year, the Pigskin Club of Washington, D.C. Offensive Player of the Year, and the Touchdown Club of Columbus (Ohio) Player of the Year. In addition to the Walter Camp Award, Bush also won the Doak Walker Award, which is given to the nation's best running back. He led the nation with an average of 222.3 all-purpose yards per game and finished fourth in the NCAA Division I-A ranks with an average of 133.85 rushing yards per game. He set the Pac-10 record for total yards from scrimmage with 513 (294 rushing, 68 receiving, 151 return) in a game against the Fresno State Bulldogs on November 19, 2005.
Bush led the Trojans with 1,740 yards on 200 carries (8.7 avg) with sixteen touchdowns and ranked third on the squad with 39 receptions for 481 yards (12.9 avg), including a pair of scores as a junior. He returned 18 punts for 179 yards (9.9 avg) and a touchdown, and gained 493 yards on 28 kickoff returns (17.6 avg).
Bush started only fourteen times in 39 games at USC. However, he finished tenth in NCAA Division I-A history with 6,541 all-purpose yards, racking up 3,169 yards and 25 touchdowns on 433 carries (7.3 avg) and 1,301 yards with thirteen scores on 95 catches (13.7 avg). Bush returned 67 kickoffs for 1,522 yards and a touchdown, adding 559 yards and three scores on 44 punt returns (12.7 avg). He also completed one of three pass attempts for a 52-yard touchdown.
The Heisman Trophy Trust conducted its own investigation of Bush's case in the summer of 2010. On September 7, the Trust's spokesman Rob Whalen denied published reports that they planned to strip the award from Bush. This would have been the first time that a Heisman Trophy had been revoked. On September 14, Bush stated he would voluntarily forfeit his award and sent the trophy back to the Heisman Trust, which then vacated the award. However, to date, neither Bush nor his family have returned his 2005 Heisman Trophy. The San Diego Hall of Champions sports museum has since given the copy of the award it had in its possession back to Bush's parents.
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When head coach Pete Carroll recruited Bush for USC, he envisioned using Bush as a five-way threat. The freshman quickly proved effective in carrying, catching, throwing and returning the ball. Bush was a consensus First-team Freshman All-American selection in 2003, and became the first Trojan since Anthony Davis in 1974 to lead the Pac-10 in kickoff returns. His 1,331 all-purpose yards set a USC freshman record. The ESPN Pac-10 Newcomer of the Year also amassed 521 yards rushing that year, with three touchdowns on 90 carries.
In 2004, Bush finished fifth in the voting for the Heisman Trophy and was named the team's MVP. He earned consensus All-American honors and was a finalist for the Walter Camp Player of the Year Award. He finished second on the team with 143 carries for 908 yards (6.3 avg) and six touchdowns, adding 509 yards and seven scores on 43 receptions (11.8 avg). Bush returned 21 kickoffs for 537 yards (25.6 avg) and 24 punts for 376 yards (15.7 avg) and a pair of touchdowns. He became the first Trojan since Marcus Allen to lead the Pac-10 in all-purpose yardage, totaling 2,330 yards. He also threw for one touchdown, tossing a 52-yard scoring strike.