As a junior in 1988, he compiled what is widely considered the greatest individual season by a running back in college football history, rushing for 2,628 yards and 37 touchdowns in 11 games.

While still performing at a high level, Sanders unexpectedly retired from professional football in 1999, at the age of 31, and 1,457 yards short of breaking the NFL's then all-time rushing record held by Walter Payton.

A year later, Sanders was inducted into the Oklahoma Sports Hall of Fame with former college teammate Thurman Thomas.

[8] Mitch Albom of the Detroit Free Press wrote: "All day they would labor, with the hammers, with the tar, sweating in the hot summer sun.

Oklahoma Sooners head coach Barry Switzer in particular told his players not to injure Thomas, in fear of Sanders starting in his place, telling them: "You won't touch this kid".

[37] Sanders ran for 222 yards and scored five touchdowns in just three quarters of action in the 1988 Holiday Bowl, a game that is not included in the official NCAA season statistics.

[39] Sanders learned of his Heisman Trophy win while he was with the team in Tokyo, Japan preparing to face Texas Tech in the Coca-Cola Classic, accepting the award via satellite;[40] he garnered 559 first-place votes for 1,878 points, becoming the eighth non-college senior to attain the trophy, and was selected as a unanimous All-American.

[63] In his first career professional game against the Phoenix Cardinals on September 10, Sanders ran for 71 yards on nine attempts and scored a rushing touchdown in the 16–13 loss.

[64][65] Against the Chicago Bears, Sanders compiled 126 yards on 18 attempts and a touchdown in the 47–27 loss, but became injured with bruised ribs and a hip pointer that plagued him through the rest of the season.

[72] During the game, the Lions installed a special phone line in one of the press boxes to monitor Christian Okoye, a running back for the Kansas City Chiefs who, at the time, was tied with Sanders for the league rushing title.

[1][79] The Lions struggled that season, posting a 7–9 record and failing to make the postseason, despite winning five straight games to end the year.

[80] On September 9, 1990, against the Tampa Bay Buccaneers, Sanders had 79 yards from 14 rushing attempts and a goal-line touchdown in the 38–21 loss in the Lions' regular season opener.

[83] On November 4, playing against the Washington Redskins, Sanders had 11 rushes for 104 yards and a touchdown, in a game where the Lions surrendered a 21-point lead to lose 38–41.

[56][95] On September 1, 1991, Sanders was inactive for the Lions' 45–0 shutout loss against the Washington Redskins, due to having sore ribs before the opening kickoff.

[96] On November 24, 1991, against the Minnesota Vikings, Sanders dominated, with 220 rushing yards on 23 attempts and four touchdowns, a game the Lions won 34–14.

[97] Sanders dedicated the win to teammate Mike Utley, who suffered a career-ending spinal cord injury the previous game.

[20][103][104] In the NFC Championship Game, Sanders was held to eleven attempts for 44 yards in the Lions' blowout 41–10 loss to the eventual Super Bowl-winning Redskins.

[111][112] The Lions revealed after the game that Sanders had suffered a torn medial collateral ligament (MCL), and would miss three to five weeks.

[56] The Lions faced the Green Bay Packers again in the Wild Card Round, after being defeated by them the previous season.

On December 31, Sanders struggled against the Packers and recorded what is viewed as the worst game of his career, having 13 attempts for -1 rushing yards.

[145][146][147] The Lions regressed, posting a 5–11 record, and failed to make the postseason after three straight playoff seasons from 1993 to 1995; though Sanders still made the Pro Bowl and was named an AP second-team All-Pro.

[153][149] Sanders reached the 2,000 mark on a two-yard run; finishing the game with 23 attempts for 184 yards and a touchdown; helping the Lions edge the Jets 13–10.

[158] Sanders had 18 attempts for 65 yards as the Lions lost 10–20 in the Wild Card Round, after quarterback Scott Mitchell left the game with an injury in the third quarter.

On July 27, 1999, Sanders announced his retirement from pro football, the day before Lions training camp was set to start.

[171] Before the ruling, Sanders offered to pay back the entire bonus in return for him being traded to another team or his release.

It was more his frustration with the management and direction of the Lions and the resulting lack of success that contributed to his retirement, as Sanders revealed in his autobiography: "My retirement letter didn't even hint at my frustration, because I didn't want to take shots at people as I left ... Management had let quality players slip away.

"[172] Sanders has since patched things up with the Lions, rejoining the organization in a paid role as a team ambassador in 2017, and they dedicated a bronze statue to him outside Ford Field in September 2023.

[187][1] Sanders was a notable bright spot on a Lions franchise that had endured years of unsuccessful play, helping to lead the team to their first playoff victory in decades.

[209] He and his wife, Lauren Campbell Sanders, a former news anchor for WDIV in Detroit, filed for divorce in February 2012 after 12 years of marriage.

[210] Sanders' brother, Byron, was the starting running back at Northwestern University, and would be selected by the Chicago Bears in the 9th round of the 1989 NFL draft.