Originally attaining a public profile in sports as a running back at the collegiate and professional levels, Simpson was the first NFL player to rush for more than 2,000 yards in a season, a mark he set during the 1973 season. While five other players have passed the 2,000 rush yard mark he stands alone as the only player to ever rush for more than 2,000 yards in a 14-game season (the NFL changed to a 16-game season in 1978). He also holds the record for the single season yards-per-game average which stands at 143.1 ypg. Simpson was elected to the Pro Football Hall of Fame in 1985.

In 1995, Simpson was acquitted of the murder of Nicole Brown Simpson and Ronald Goldman after a lengthy, internationally publicized criminal trial — the People v. Simpson. A 1997 judgment against Simpson for their wrongful deaths was awarded in civil court in a case which he did not actively defend, but to date he has paid little of the $33.5 million judgment. His book, If I Did It (2006), related to the murders, purports to be a first-person fictional account of the murder had he actually committed it, was withdrawn by the publisher just before its release. The book was later released by the Goldman family.

In September 2007, Simpson was arrested in Las Vegas, Nevada, and charged with numerous felonies, including armed robbery and kidnapping. In 2008 he was found guilty, and sentenced to at least nine years in prison. He is currently serving his sentence at the Lovelock Correctional Center in Lovelock, Nevada.

Simpson was born in San Francisco, California, the son of Eunice (née Durden; October 23, 1921 – San Francisco, California, November 9, 2001), a hospital administrator, and Jimmy Lee Simpson (Arkansas, January 29, 1920 – San Francisco, California, June 9, 1986), a chef and bank custodian. Simpson's maternal grandparents were from Louisiana. His aunt gave him the name Orenthal, which supposedly was the name of a French actor she liked. Simpson has one brother, Melvin Leon "Truman" Simpson, and one living sister, Shirley Simpson-Baker, and one deceased sister, Carmelita Simpson-Durio. As a child, Simpson developed rickets and wore braces on his legs until the age of five. His parents separated in 1952.

At Galileo High School in San Francisco, Simpson played for the school football team, the Galileo Lions. From 1965 to 1966, Simpson was a student at City College of San Francisco, a member of the California Community College system. He played both offense (running back) and defense (defensive back) and was named to the Junior College All-American team as a running back.

Simpson gained an athletic scholarship to the University of Southern California where he played running back in 1967 and 1968. Simpson led the nation in rushing in 1967 when he ran for 1,451 yards and scored 11 touchdowns. He also led the nation in rushing the next year with 355 carries for 1,709 yards.

In 1967, he starred in the 1967 USC vs. UCLA football game and was a Heisman Trophy candidate as a junior, but he did not win the award. His 64 yard touchdown run in the 4th quarter tied the game, with the PAT the margin of victory. This was the biggest play in what is regarded as one of the greatest football games of the 20th century.

Another dramatic touchdown in the same game is the subject of the Arnold Friberg oil painting, O.J. Simpson Breaks for Daylight. Simpson also won the Walter Camp Award in 1967 and was a two-time consensus All-American. He ran in the USC sprint relay quartet that broke the world record at the NCAA track championships in Provo, Utah in June 1967.

In 1968, he rushed for 1,709 yards and 22 touchdowns, earning the Heisman Trophy, the Maxwell Award, and the Walter Camp Award that year. He still holds the record for the Heisman's largest margin of victory, defeating the runner-up by 1,750 points. In the 1969 Rose Bowl where #2 USC faced #1 Ohio State, Simpson ran for 171 yards, including an 80-yard touchdown run in a 16-27 loss to top ranked Ohio State.

The October 27, 1968 regular-season NFL game between the Philadelphia Eagles and the Pittsburgh Steelers was dubbed the "O.J. Bowl", as it was thought the loser would be awarded the first pick in the 1969 NFL Draft and thereby secure Simpson for the following season. The Steelers won 6–3 (on 2 field goals by Booth Lusteg), however, neither team captured the first draft pick.