Simpson's maternal grandparents were from Louisiana, and his aunt gave him the name Orenthal, which she said was the name of a French actor she liked. Simpson has one brother, Melvin Leon "Truman" Simpson, 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, giving him his bowlegged stance. His parents separated in 1952, and Simpson was raised by his mother.

Although Simpson was an All-City football player at Galileo, his mediocre high-school grades prevented him from attracting the interest of many college recruiters. After a childhood friend's injury in the Vietnam War influenced Simpson to stay out of the military, he enrolled at City College of San Francisco in 1965. He played football both ways as a running back and defensive back and was named to the Junior College All-American team as a running back. City College won the Prune Bowl against Long Beach State, and many colleges sought Simpson as a transfer student for football.

At age 19 on June 24, 1967, Simpson married Marguerite L. Whitley. Together, they had three children: Arnelle L. Simpson (b. 1968), Jason L. Simpson (b. 1970), and Aaren Lashone Simpson (1977–1979). In August 1979, Aaren drowned in the family's swimming pool.

As a senior in 1968, Simpson rushed for 1,709 yards and 22 touchdowns in the regular season, earning the Heisman Trophy, the Maxwell Award, and Walter Camp Award. He still holds the record for the Heisman's largest margin of victory, defeating runner-up Leroy Keyes by 1,750 points. In the Rose Bowl on New Year's Day, #2 USC faced top-ranked Ohio State; Simpson ran for 171 yards, including an 80-yard touchdown run in a 27–16 loss.

The first selection 1969 AFL-NFL Common Draft was held by the AFL's Buffalo Bills, after finishing 1–12–1 in 1968. They took Simpson, but he demanded what was then the largest contract in professional Sports history: $650,000 over five years. This led to a standoff with Bills' owner Ralph Wilson, as Simpson threatened to become an actor and skip professional football. Eventually, Wilson agreed to pay Simpson.

Simpson entered professional football with high expectations, but struggled in his first three years, averaging only 622 yards per season. Bills coach John Rauch, not wanting to build an offense around one running back, assigned Simpson to do blocking and receiving duties at the expense of running the ball. In 1971, Rauch resigned as head coach and the Bills brought in Harvey Johnson. Despite Johnson devising a new offense for Simpson, Simpson was still ineffective that year. After the 1971 season, the Bills fired Johnson and brought in Lou Saban as head coach. Unlike Rauch, Saban made Simpson the centerpiece of the Bills offense.

In 1972, Simpson rushed for over 1,000 yards for the first time in his career, gaining a league-leading total of 1,251 yards. In 1973, Simpson became the first player to break the highly coveted 2,000 yard rushing mark, with 2,003 total rushing yards and 12 touchdowns. Simpson broke the mark during the last game of the season against the New York Jets with a 7-yard rush. That same game also saw Simpson break Jim Brown's single-season rushing record of 1,863 yards. For his performance, Simpson won that year's NFL MVP Award and Bert Bell Award. While other players had broken the 2,000-yard mark since Simpson, this record happened back when the NFL only had 14-game seasons, as opposed to the 16-game seasons since the 1978 season.

Simpson gained 11,236 rushing yards, placing him 2nd on the NFL's all-time rushing list when he retired; he now stands at 21st. He was named NFL Player of the Year in 1973, and played in six Pro Bowls. He was the only player in NFL history to rush for over 2,000 yards in a 14-game season and he's the only player to rush for over 200 yards in six different games in his career. From 1972 to 1976, Simpson averaged 1,540 rushing yards per (14 game) season, 5.1 yards per carry, and he won the NFL rushing title four times. Simpson was inducted into the Pro Football Hall of Fame in 1985, his first year of eligibility.

Simpson played in only one playoff game during his 11-season Hall of Fame career: a 1974 Divisional Playoff between the Buffalo Bills and the Pittsburgh Steelers. Simpson was held to 49 rushing yards, 3 receptions for 37 yards, and one touchdown, and the Bills lost 14-32 to the team which went on to win Super Bowl IX.

In 1975, People magazine described Simpson as "the first black athlete to become a bona fide lovable media superstar." Chuck Barnes helped him form Business relationships with Chevrolet and ABC early in his career. By 1971, New York wrote that Simpson was already wealthy enough to, "retire this week if [he] wanted to." His amiable persona and natural charisma landed Simpson numerous endorsement deals. From 1975, he appeared in advertisements with the Hertz rental car company, in whose commercials he was depicted running through airports, serving as an embodiment of speed; Simpson estimated that the very successful campaign raised the recognition rate among people he met from 30% to 90%. He was also a longtime spokesman for Pioneer Chicken and owned two franchises, one of which was destroyed during the 1992 Los Angeles riots; as well as HoneyBaked Ham, the pX Corporation, and Calistoga Water Company's line of Napa Naturals soft drinks. He also appeared in comic book ads for Dingo Cowboy boots.

Simpson met Nicole Brown in 1977, while she was working as a waitress at the nightclub "The Daisy". Although still married to his first wife, Simpson began dating Brown. Simpson and Marguerite divorced in March 1979.

Before the 1978 season, the Bills traded Simpson to his hometown San Francisco 49ers for a series of draft picks. Simpson played in San Francisco for two seasons, rushing for 1,053 yards and four touchdowns. His final NFL game was on December 16, 1979, a 31–21 loss to the Atlanta Falcons at Atlanta–Fulton County Stadium. His final play was a 10-yard run on 3rd and 10 for a first down.

Simpson was inducted into the College Football Hall of Fame in 1983 and the Pro Football Hall of Fame in 1985. After retiring from football, he began new careers in acting and football broadcasting.

Brown and Simpson were married on February 2, 1985, five years after his retirement from professional football. The couple had two children, Sydney Brooke Simpson (b. 1985) and Justin Ryan Simpson (b. 1988). The marriage lasted seven years, during which Simpson pleaded no contest to spousal abuse in 1989. Brown filed for divorce on February 25, 1992, citing irreconcilable differences. In 1993, after the divorce, Brown and Simpson made an attempt at reconciliation, but according to Sheila Weller "they were a dramatic, fractious, mutually obsessed couple before they married, after they married, after they divorced in 1992, and after they reconciled."

In the late 1990s, Simpson attempted to register "O.J. Simpson", "O.J.", and "The Juice" as trademarks for "a broad range of goods, including figurines, trading cards, sportswear, medallions, coins, and prepaid telephone cards." A "concerned citizen", william B. Ritchie, sued to oppose the granting of federal registration on the grounds that doing so would be immoral and scandalous. Simpson gave up the effort in 2000.

On June 12, 1994, Nicole Brown Simpson and Ron Goldman were found stabbed to death outside Nicole's condominium in the Brentwood area of Los Angeles. Simpson was a person of interest in their murders. Simpson did not turn himself in, and on June 17 he became the object of a low-speed pursuit in a white 1993 Ford Bronco SUV owned and driven by Al Cowlings. TV stations interrupted coverage of the 1994 NBA Finals to broadcast the incident live. With an estimated audience of 95 million people, the event was described as "the most famous ride on American shores since Paul Revere's". The pursuit, arrest, and trial were among the most widely publicized events in American history. The trial, often characterized as the Trial of the Century because of its international publicity similar to that of Sacco and Vanzetti and the Lindbergh kidnapping, culminated after eleven months on October 3, 1995, when the jury rendered a verdict of "not guilty" for the two murders. An estimated 100 million people nationwide tuned in to watch or Listen to the verdict announcement. Following Simpson's acquittal, no additional arrests or convictions related to the murders were made.

Following Simpson's acquittal of Criminal charges, Ron Goldman's family filed a civil lawsuit against Simpson. Daniel Petrocelli represented plaintiff Fred Goldman (Ronald Goldman's father), while Robert Baker represented Simpson. Superior Court Judge Hiroshi Fujisaki presided, and he barred television and still cameras, radio equipment, and courtroom Sketch artists from the courtroom. On October 23, 1996, opening statements were made, and on January 16, 1997, both sides rested their cases.

In 1997, Simpson was evicted from the estate in which he had lived for 20 years, at 360 North Rockingham Avenue, after defaulting on the mortgage. In July 1998, the house was demolished by its next owner, Kenneth Abdalla, an investment banker and President of the Jerry's Famous Deli chain. The property's address has since been renumbered to 380 North Rockingham Avenue.

The State of California claims Simpson owes $1.44 million in back taxes. A tax lien was filed in his case on September 1, 1999.

A 2000 Rolling Stone article reported that Simpson still made a significant income by signing autographs. He subsequently moved from California to Florida, settling in Miami. In Florida, among a few states, a person's residence cannot be seized to collect a debt under most circumstances.

On December 4, 2001, Simpson's Miami home was searched by the FBI on suspicion of ecstasy possession and money laundering. The FBI had received a tip that Simpson was involved in a major drug trafficking ring after 10 other suspects were arrested in the case. Simpson's home was thoroughly searched for two hours, but no illegal drugs were discovered, and no arrest or formal charges were filed following the search. However, investigators uncovered equipment capable of stealing satellite television programming, which eventually led to Simpson's being sued in federal court.

On July 4, 2002, Simpson was arrested in Miami-Dade County, Florida, for water speeding through a manatee protection zone and failing to comply with proper boating regulations. The misdemeanor boating regulation charge was dropped, and Simpson was fined for the speeding infraction.

In March 2004, satellite television network DirecTV, Inc. accused Simpson in a Miami federal court of using illegal electronic devices to pirate its broadcast signals. The company later won a $25,000 judgment, and Simpson was ordered to pay an additional $33,678 in attorney's fees and costs.

On September 5, 2006, Goldman's father took Simpson back to court to obtain control over Simpson's "right to publicity", for purposes of satisfying the judgment in the civil court case. On January 4, 2007, a federal judge issued a restraining order prohibiting Simpson from spending any advance he may have received on a canceled book deal and TV interview about the 1994 murders. The matter was dismissed before trial for lack of jurisdiction. On January 19, 2007, a California state judge issued an additional restraining order, ordering Simpson to restrict his spending to "ordinary and necessary living expenses".

On November 8, 2007, Simpson had a preliminary hearing to decide whether he would be tried for the charges. He was held over for trial on all 12 counts. Simpson pleaded not guilty on November 29, and the trial was reset from April to September 8, 2008. Court officers and attorneys announced, on May 22, 2008, that long questionnaires with at least 115 queries would be given to a jury pool of 400 or more.

Simpson faced a possible life sentence with parole on the kidnapping charge, and mandatory prison time for armed robbery. On December 5, 2008, Simpson was sentenced to a total of thirty-three years in prison, with the possibility of parole after nine years, in 2017. On September 4, 2009, the Nevada Supreme Court denied a request for bail during Simpson's appeal. In October 2010, the Nevada Supreme Court affirmed his convictions. He served his sentence at the Lovelock Correctional Center where his inmate ID number was #1027820.

A Nevada judge agreed on October 19, 2012, to ″reopen the armed robbery and kidnapping case against O. J. Simpson to determine if the former football star was so badly represented by his lawyers that he should be freed from prison and get another trial.″ A hearing was held beginning May 13, 2013, to determine if Simpson was entitled to a new trial. On November 27, 2013, Judge Linda Bell denied Simpson′s bid for a new trial on the robbery conviction. In her ruling, Bell wrote that all of Simpson′s contentions lacked merit.

On July 31, 2013, the Nevada Parole Board granted Simpson parole on some convictions, but his imprisonment continued based on the weapons and assault convictions. The board considered Simpson's prior record of Criminal convictions and good behavior in prison in coming to the decision. At his parole hearing on July 20, 2017, the board decided to grant Simpson parole. He was released on October 1, 2017, having served nine years.

According to a 2016 poll, 83% of white Americans and 57% of black Americans believe Simpson was guilty of the murders.

In 2007, Simpson was arrested in Las Vegas, Nevada, and charged with the felonies of armed robbery and kidnapping. In 2008, he was convicted and sentenced to 33 years imprisonment, with a minimum of nine years without parole. He served his sentence at the Lovelock Correctional Center near Lovelock, Nevada. On July 20, 2017, Simpson was granted parole. He was eligible for release from prison on October 1, 2017, and was released shortly after midnight on that date.