In the 1972 NFL Draft he was picked up by the Pittsburgh Steelers in the first round, the 13th selection overall. His selection by the team was considered controversial at the time, as many thought the team would select his Penn State teammate, Lydell Mitchell. (Mitchell was later selected by the Baltimore Colts in the draft.) He played his first 12 years in the NFL with the Steelers; his 13th and final year (1984) was spent with the Seattle Seahawks. He was inducted into the Pro Football Hall of Fame in 1990. He was inducted into the New Jersey Hall of Fame in 2011.
In his first season with the Steelers (1956), 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.
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.
Harris was chosen for 9 consecutive Pro Bowls (from 1972 through 1980), and was All-Pro in 1977. Harris rushed for more than 1,000 yards in 8 seasons, breaking a record set by Jim Brown. The tandem running package of Harris and Rocky Bleier combined with a strong defense to win four Super Bowls in the 1975, 1976, 1979, and 1980 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, including Jim Brown, have complained about Harris's tendency to run out of bounds instead of taking on tacklers for extra yards. Harris responds that he extended his career and thus his contribution to the team's objectives (including four Super Bowl victories to Brown's single pre-Super Bowl NFL Championship) by avoiding unnecessary contact.
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; in 2006, during pre-game ceremonies for Super Bowl XL (the Steelers' second SB appearance - and first championship - since his retirement) honoring the MVPs of the previous 39 games, Harris waved a Terrible Towel while being introduced, much to the delight of the overwhelmingly pro-Steeler crowd. 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.
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 into the endzone 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. Raiders linebacker Phil Villapiano attempted to criticize Harris's achievement by stating that he was only in position to catch the ball because he was lazy, but replays show that Harris 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.
Harris and Lydell Mitchell, successful college teammates at Penn State, now own Super Bakery, a company founded in 1990 to produce nutrition-oriented foods for schoolchildren. The business was renamed to RSuper Foods in 2006. RSuper foods produces the Super Donut that has been served to students at public schools in the eastern United States.
Harris and Mitchell also partnered in 1996 to rescue the Parks Sausage Company in Baltimore, the first African-American owned business to go public in the U.S.
In John Grisham's 2008 novel Playing For Pizza, the fullback of the Parma Panthers is nicknamed Franco as a tribute to his hero, Franco Harris, who he refers to as the "greatest Italian football player". This is a reference to Franco's mixed racial heritage.
On July 27, 2009 Harris' son, Franco "Dok" Harris, officially announced his candidacy for Mayor of the City of Pittsburgh. He placed second in the general election on November 3 of that year, receiving 25% of the vote.