Reggie Bush was a big part of the BCS National Championship-winning Trojans team in 2004. The electric runner was twice named a consensus All-American over three years at USC (2004, 2005), and would go on to win the 2005 Doak Walker and Walter Camp awards, as well as the Heisman Trophy. However, allegations he received improper benefits at the university would lead to the forfeiture of college football's most prestigious award. Bush would leave USC with 4,470 yards from scrimmage and 38 all-purpose touchdowns.

As one of the top prospects in the country, Bush, a junior, declared for the 2006 NFL Draft. He blazed 4.33 and 4.37 40-yard-dash times for NFL scouts at his USC Pro Day in Los Angeles on April 2, 2006. He would be selected by the New Orleans Saints with the No. 2 overall pick, sandwiched between NC State defensive end Mario Williams (No. 1, Texans) and Texas quarterback Vince Young (No. 3, Titans). The first round Bush was part of featured 16 players that would go on to earn Pro Bowl selections.

Bush would join All-Pro quarterback Drew Brees as a figure in Sean Payton's "Air Coryell" offense. He was part of a backfield-by-committee that featured runners such as Duece McAllister, Pierre Thomas and Chris Ivory. Bush accrued 2,090 rushing yards on 524 attempts in New Orleans (4.0 YPC), and 29 all-purpose touchdowns. He would win a Super Bowl in 2009.

On July 28, 2011, the Saints traded Bush to the Miami Dolphins for backup safety Jonathon Amaya and a swap of sixth-round draft picks. He started all 31 games played over the 2011 and 2012 seasons, racking up 2,072 rushing yards and 12 rushing touchdowns during his time there. He scored three more times in the air. In 2011, his debut year in Miami, Bush ripped off his first 1,000-yard season as a feature back. He averaged 4.7 yards per carry for the Dolphins.

On March 13, 2013, Bush signed a four-year, $16 million contract with the Detroit Lions. In his first game, he ran for 90 yards and added another 101 in the air, scoring a touchdown in a home win over the division rival Vikings. Bush would achieve his second career 1,000-yard campaign that season. He had 1,512 yards from scrimmage and seven total touchdowns. His second season was a disappointment, as Bush's production fell dramatically. He appeared in 11 games and ran for just 297 yards on 76 carries. On February, 25, 2015, the 29-year-old tailback was released by the Lions.

On March 14, 2015, Bush agreed to join the San Francisco 49ers. He drew interest from the New Orleans Saints and New England Patriots, but announced that he would be a 49er, saying on Twitter: "The best is yet to come #49ers." Bush joins a backfield that expects to feature young runners in Carlos Hyde and Kendall Hunter.