In 1972, Griffin was a T-formation halfback, and from 1973 through 1975, he was the team’s I-formation tailback. He led the Buckeyes in rushing as a freshman with 867 yards, but his numbers exploded the following year with the team’s conversion to the I-formation. He rushed for 1,428 yards in the regular season as a sophomore, 1,620 as a junior, 1,357 as a senior. Griffin is the only back to lead the Big Ten Conference in rushing for three straight years. Overall, Griffin rushed for 5,589 yards on 924 carries in his four seasons with the Buckeyes (1972–1975), then an NCAA record. He had 6,559 all-purpose yards and scored 26 touchdowns. In their four seasons with Griffin as their starting running back, the Buckeyes posted a record of 40-5-1. Griffin is one of only two players in collegiate football history to start four Rose Bowl games, the other being Brian Cushing.

In the 1976 NFL Draft, he was the first-round draft choice of the Cincinnati Bengals, selected as the 24th overall pick in the draft. Griffin played 7 seasons in the NFL, all with the Bengals (1976–1982). He was joined in the backfield with his college fullback teammate Pete Johnson, who was drafted by the Bengals in 1977, and his brother, Ohio State defensive back Ray Griffin, who was drafted by the team in 1978. During his 7 NFL seasons, he rushed for 2808 yards and 7 touchdowns, and caught 192 passes for 1607 yards and 6 touchdowns. Griffin played in Super Bowl XVI with the Bengals after the 1981 season.

The College Football Hall of Fame enshrined Griffin in 1986. Ohio State enshrined him in their own Varsity O Hall of Fame in 1981 and officially retired his number, 45, in 1999. He was inducted into the Rose Bowl Hall of Fame in 1990. In 2007, he was ranked No. 21 on ESPN’s Top 25 Players In College Football History list. On January 1, 2014, Griffin was named the All-Century Player of the Rose Bowl Game during the celebration of the 100th Rose Bowl Game and participated in the Rose Parade.

In 1996 Griffin was inducted into the high school hall of fame. Eastmoor Academy renamed their playing field “Archie Griffin Field” in his honor.

Along with former NBA basketball star Magic Johnson, Griffin was one of the investors in Mandalay Baseball Properties LLC which owned the Dayton Dragons, a class single-A minor league baseball team affiliated with Major League Baseball’s Cincinnati Reds, prior to the sale of the team in 2014 to Palisades Arcadia Baseball LLC.

As of 2020, Griffin’s son Andre is entering his first year as an assistant coach at Ohio Northern University and previously was the Head Coach at Lima Senior High School. Griffin’s son Adam played as a defensive back for the Ohio State football team for three seasons until a shoulder injury ended his football career. Griffin also has three grandsons Kamron, Diante, and Adrien.