Ingram was ruled out for the season opener after undergoing minor knee surgery the week prior to the opening game against San Jose State. Sophomore running back Trent Richardson filled in for Ingram for the first two games, after it was announced that the junior was not likely to play against Penn State on September 11. He eventually made his season debut in a road game against Duke, rushing for 151 yards on nine carries, including two touchdowns in the first quarter, as Alabama routed the Blue Devils 62–13.
Ingram finished his junior season with 875 yards on 158 carries with 13 touchdowns, with an additional 282 yards receiving and a touchdown. On January 6, 2011, Ingram announced he would forgo his senior season and enter the 2011 NFL draft. At the time of the announcement, he was projected as a first round pick. On April 19, 2011, Ingram was voted by fans to be on the Cover of NCAA Football 12 On PlayStation 3 and Xbox 360.
On August 12, 2011, Ingram scored his first career touchdown as a Saint on a 14-yard run in a preseason game against the San Francisco 49ers. On September 25, Ingram scored his first touchdown in regular season play as a Saint on a tough 13-yard run against the Houston Texans. On October 23, late in the game on Sunday Night Football in a runaway win against the Indianapolis Colts Ingram injured his heel. It was considered a 'day-to-day' injury at first, but Ingram was unable to practice the entire week and missed the following game versus the winless St. Louis Rams which ended in a 31–21 loss for the Saints. He returned to action against the Atlanta Falcons on November 13. On November 28, against the New York Giants, he finished with 80 rushing yards and a touchdown. In his final action of the 2011 season on December 4, he finished with 54 rushing yards and a touchdown against the Detroit Lions. He suffered a toe injury and missed the remainder of the season. He finished his rookie season with 474 rushing yards and five touchdowns.
Ingram was the Saints' leading rusher for the 2012 season, sharing the backfield with Pierre Thomas, Darren Sproles, and Chris Ivory. Early in the season, Ingram was part of a more balanced backfield but starting in Week 10, he earned significantly more carries. Overall, in the 2012 season, he finished with 602 rushing yards and five rushing touchdowns.
After wearing the #28 jersey for two seasons, Ingram changed to number 22, the number he wore at Alabama, before the beginning of the 2013 season. The 2013 season was one of lessened production for Ingram. He started off the season slow with only 31 combined rushing yards in the first two games. Ingram's performance was hampered by a toe injury. He returned to action on November 3, but only posted 19 rushing yards against the New York Jets. In the next game, a 49–17 win over the Dallas Cowboys, he had a career day with 145 rushing yards and a touchdown. Over the remainder of the season, he eclipsed 50 rushing yards only once, against the Carolina Panthers. Overall, in the 2013 season, he finished with 386 rushing yards and one rushing touchdown. The Saints qualified for the playoffs in the 2013 season. In the Wild Card Round against the Philadelphia Eagles, he finished with 97 rushing yards, one rushing touchdown, and 17 receiving yards in the 26–24 victory. In the Divisional Round against the Seattle Seahawks, he finished with 49 rushing yards in the 23–15 loss.
On March 7, 2015, Ingram and the Saints agreed to a four-year deal worth $16 million. In the season opener against the Arizona Cardinals, he was held to 24 rushing yards but had eight receptions for 98 receiving yards in the 31–19 loss. In Week 4, against the Dallas Cowboys, he had 128 scrimmage yards in the 26–20 victory. On October 15, against the Atlanta Falcons, he finished with 46 rushing yards and two rushing touchdowns. In the next game, a 27–21 victory over the Indianapolis Colts, he had his most productive game of the season with 143 rushing yards and a touchdown. On November 15, Ingram injured his shoulder in the Week 10 loss to the Washington Redskins. Ingram's shoulder injury sidelined him in the season's final four games. He finished the 2015 season with 769 rushing yards, six rushing touchdowns, and 405 receiving yards.
On May 8, 2018, Ingram was suspended for the first four games of the season due to violating the policy on performance-enhancing drugs. He returned in Week 5 and recorded 53 rushing yards and two rushing touchdowns in the 43–19 victory over the Washington Redskins. In Week 10 against the Cincinnati Bengals, he had 104 rushing yards, 58 receiving yards, and a receiving touchdown in the 51–14 victory. In Week 11, against the Philadelphia Eagles, he had 103 rushing yards and two rushing touchdowns. In Week 16 against the Pittsburgh Steelers, Ingram recorded his 50th touchdown, surpassing Deuce McAllister for the Saints franchise record for rushing touchdowns. Overall, in the 2018 season, Ingram had 645 rushing yards and six rushing touchdowns to go along with 21 receptions for 170 receiving yards and one receiving touchdown. The Saints won the NFC South and had home-field advantage throughout the NFC Playoffs as the #1-seed. In the Divisional Round against the Philadelphia Eagles, Ingram had 53 rushing yards in the 20–14 victory. In the NFC Championship against the Los Angeles Rams, he had 31 rushing yards in the 26–23 overtime loss. He was ranked 80th by his fellow players on the NFL Top 100 Players of 2019.
On October 29, 2021, Ingram was traded back to the Saints in exchange for a 2024 seventh-round pick. Ingram became the New Orleans Saints' all-time rushing yards leader in the 2021 NFL season in Week 10, against the Tennessee Titans, surpassing the previous record holder, Deuce McAllister. He finished the 2021 season with 160 carries for 554 rushing yards and two rushing touchdowns to go along with 27 receptions for 162 receiving yards.
On October 31, 2022, it was announced that Ingram would miss 3–4 weeks after suffering a grade 2 MCL sprain against the Las Vegas Raiders in Week 8. He was placed on injured reserve on December 14. In the 2022 season, Ingram appeared in ten games and started three. He finished with 62 carries for 233 rushing yards and one rushing touchdown.
On July 6, 2023, Ingram announced his retirement from playing football along with his decision to join Fox Sports' Big Noon Kickoff show.
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