Jackson's subsequent success has been credited with prompting college football programs to take more interest in players in the Las Vegas area. This success also led to Jackson's induction into the Southern Nevada Sports Hall of Fame in 2011.
Jackson attended Oregon State University, where he played for the Oregon State Beavers football team for three seasons. In 36 games, he carried 743 times for 3,625 yards for a 4.9-yard average and 39 touchdowns while adding 680 yards and 6 touchdowns on 66 catches and 240 yards with a touchdown on 7 kickoff returns. His 4,545 all-purpose yards rank second in school history, while he ranks third on the school’s all-time scoring list with 276 points. As a junior he ranked tenth in the nation in rushing, ninth in all-purpose yardage, and fourth in scoring; he carried the ball 350 times for 1,545 yards and 19 touchdowns, adding 44 receptions for 470 yards and 3 touchdowns. His 2,015 all-purpose yards set a school record. As a sophomore Jackson led the Pac-10 Conference in rushing and finished the season eighth nationally with 1,690 yards, an average of 130 yards per game.
Jackson was overlooked by several teams in 2004, most likely due to a knee injury suffered during his last year at Oregon State - an injury that kept him from participating in drills at the 2004 NFL Combine. Jackson had surgery on the knee after the college season, but required additional clean-up surgery after his rookie year to ensure its complete rehabilitation. In an interview with CBS Sports' Pete Prisco on how the knee injury had affected his play, Jackson said "I never felt right. Now it does."
On July 30, 2004, Jackson signed a 5-year, $7 million deal with the Rams, which included a $2.05 million signing bonus. In his 2004 rookie season, he was a backup under Marshall Faulk. Despite the limited playing time, he rushed 134 times for 673 rushing yards and 4 touchdowns, and had 19 receptions for 189 yards.
With Faulk aging, Jackson was named the Rams' starting running back for the 2005 season. Jackson had 1,046 rushing yards and 8 touchdowns on 254 attempts, and caught 43 passes for 320 yards and 2 touchdowns.
After the dismissal of head coach Mike Martz, 2006 became Jackson's breakout season. With Scott Linehan as the new head coach, the Rams had a more balanced offensive attack. Jackson ran 346 times for 1,528 yards and 13 touchdowns and led all running backs when he caught 90 passes for 806 yards, and adding 3 touchdowns. He also led the NFL in total yards from scrimmage with 2,334. For his efforts, Jackson was named to his first Pro Bowl and received one vote for the 2006 NFL Offensive Player of the Year award. He was also named the Rams MVP of 2006.
During the Rams' dismal 2007 season, Jackson lashed out at fans and expressed distaste with the music played in the Edward Jones Dome. After the season, with one year left on his rookie contract, Jackson believed he was underpaid and held out of training camp. On August 21, 2008, Jackson officially ended his holdout by signing a six-year contract worth a maximum of $49.3 million, including a $11.4 million signing bonus and $21 million guaranteed. Because the final two years of the deal (the 2012 & 2013 seasons) can be voided based on Jackson's performance, it could become a three-year extension worth $29.3 million instead. Either way, signing the contract made him the highest-paid running back in the NFL.
On October 24, 2010, Jackson surpassed Eric Dickerson as the Rams' all-time leading rusher, with a 110-yard effort against the Tampa Bay Buccaneers. Then on November 21, 2010, he recorded his 10,000th career yard from scrimmage on a first quarter run against the Atlanta Falcons. Jackson rushed for 1,145 yards during the 2011 Regular Season, marking the seventh consecutive season he has surpassed 1,000 yards.
On December 16th, 2012, against the Minnesota Vikings, Jackson became the 27th running back in NFL history to rush for over 10,000 yards. On December 30th, 2012, at the Seattle Seahawks, he became only the 6th running back in league history to compile 8 consecutive 1000-yard rushing seasons. Jackson ended the 2012 season with 1,042 yards rushing and 4 Touchdowns, helping St. Louis to a 7-8-1 record. In February 2013, the Rams allowed Jackson to void the final year of his six-year contract signed in 2007, even though he had not met the requirements to do so, making him a free agent following the end of the season.