Franco Harris was born in Fort Dix, New Jersey. His father is an African-American man who served in World War II; his mother was a "war bride" from Italy. Harris went to Rancocas Valley Regional High School in Mount Holly Township, New Jersey, and then attended Penn State University. While playing for the Penn State Nittany Lions, Harris served primarily as a blocker for the Nittany Lions' All-American running back Lydell Mitchell.

In his first season with the Steelers (1972), Harris was named the league's rookie of the year by both The Sporting News and United Press International. In that season he gained 1,055 yards on 188 carries, with a 5.6 yards per carry average. He also rushed for 10 touchdowns and caught 3 touchdown passes. He was popular with Pittsburgh's large Italian-American population: his fans dubbing themselves "Franco's Italian Army" and wore army helmets with his number on them.

Franco Harris was chosen for 9 consecutive Pro Bowls from 1972 through 1980, and was All-Pro in 1977. He broke Jim Brown's record by rushing for more than 1,000 yards in 8 seasons. The tandem running package of Harris and Rocky Bleier combined with a strong defense to win four Super Bowls in the 1974, 1975, 1978, and 1979 seasons. In 1975 he was the Most Valuable Player of Super Bowl IX; in that game he rushed for 158 yards and a touchdown on 34 carries for a 16-6 win over the Minnesota Vikings. Harris was the first African American as well as the first Italian-American to be named Super Bowl MVP. Harris was a major contributor for the Steelers in all of their first four Super Bowl wins. His Super Bowl career totals of 101 carries for 354 yards are records and his 4 career rushing touchdowns are tied for the second most in Super Bowl history.

Critics (especially Jim Brown) complained about Harris' tendency to run out of bounds instead of taking on tacklers for extra yards, something that years later would be attributed to Seattle Seahawks running back Shaun Alexander. Harris felt that he extended his career by avoiding unnecessary contact. Harris also had a tendency to fumble the football tallying 90 total career fumbles - the most all time for a running back.

In his 13 professional seasons, Harris gained 12,120 yards on 2,949 carries, a 4.1 yards per carry average, and scored 91 rushing touchdowns. He caught 307 passes for 2,287 yards, a 7.4 yards per reception average, and 9 receiving touchdowns. Harris's 12,120 career rushing yards rank him 12th all time in the NFL, while his 91 career rushing touchdowns rank him 10th all time tied with Jerome Bettis. While the Steelers no longer officially retire uniform numbers, they have not reissued his number 32 since he left the team, and it is generally understood that no Steelers player will ever wear that number again.

Following the 1983 season, Harris and Walter Payton were both closing in on Jim Brown's NFL rushing record, and Harris had asked the Rooney family for a pay raise. The Rooney family refused, believing that Harris was on the downside of his career, and Harris threatened to hold out. The Steelers released Harris in training camp in 1984, which would start similar patterns years later with Rod Woodson and Alan Faneca both asking similar demands before leaving in free agency. (Free agency, as it is seen today in the NFL, was not in existence at the time of Harris's release.) Harris would sign with the Seattle Seahawks during the 1984 season and would play eight games with the team, earning only 170 yards before retiring (192 yards short of Jim Brown's record). Harris and the Rooneys reconciled after Harris retired.

Franco Harris was a key player in one of professional football's most famous plays, dubbed "The Immaculate Reception" by Pittsburgh sportscaster Myron Cope. In a 1972 playoff game, the Oakland Raiders were leading the Steelers 7-6 with 22 seconds to play when a Terry Bradshaw pass was deflected away from intended receiver John "Frenchy" Fuqua right as defender Jack Tatum arrived to tackle Fuqua. Harris snatched the ball just before it hit the ground and ran it in to win the game. The Raiders challenged the touchdown, claiming that Fuqua had handled the ball before Harris, which would invalidate the score because at that time it was against the rules for two offensive receivers to touch the ball. The Steelers maintained that the ball had touched Tatum instead. According to a recounting by the Pro Football Hall of Fame, the film of the play is inconclusive. (Later controversy stemming from Raiders linebacker Phil Villapiano's assertion that Harris was only in position to catch the ball because he was lazy is widely discounted. Harris' original assignment on the play was to block, but he headed downfield when the Raiders forced Bradshaw out of the pocket, and can be clearly seen running before catching the deflected ball.)

In 1999, he was ranked number 83 on The Sporting News' list of the 100 Greatest Football Players.

In 2006, The Heinz History Center, home of the Western Pennsylvania Sports Museum, installed a life-size figure of Harris in the grand concourse of Pittsburgh International Airport. The statue is a recreation of Harris' "Immaculate Reception."