His jersey number was retired by the Bandits in 2008. While with the Bandits in 2004, Jackson's childhood home in Arlington, Texas, was torn down to make way for Cowboys Stadium, which replaced Texas Stadium as the home of the Dallas Cowboys in 2009. Jackson played in his former neighborhood on November 13, 2011, when the Bills faced the Cowboys. Jackson played in NFL Europa for the Rhein Fire in 2006, leading the team with 731 rushing yards. Jackson was invited to training camp with the Buffalo Bills in 2006 by Bills general manager Marv Levy, a Coe College alumnus himself. He made his first career start against the Washington Redskins in 2007, rushing for 82 yards while catching four passes for 69 yards in a Bills victory. He became the first Division III running back to start an NFL game since December 24, 2000, when former Ferrum College running back Chris Warren started for the Philadelphia Eagles against the Cincinnati Bengals. In a 2007 victory over the Miami Dolphins, Jackson rushed for 115 yards with a long of 27 yards to top the 100-yard rushing mark for the first time in his NFL career. Teammate Marshawn Lynch rushed for 107 yards, marking the first time the Buffalo Bills had two players rush for 100-plus yards in the same game since 1996 when Thurman Thomas and Darick Holmes accomplished the feat. Before the 2009 season, Jackson signed a four-year contract extension to stay with the Bills. At the end of the 2009 season, after winning the starting job from Lynch in Week 12, Jackson eclipsed the 1,000-yard rushing mark for the first time in his career with 1,062 yards and 2 touchdowns. He also set a career-high in catches with 46 for 371 yards and 2 more scores and also completed a 27-yard touchdown pass. Jackson also had 1,014 kickoff return yards making him the first player in NFL history to compile 1,000 rushing and 1,000 kickoff return yards. The 2,516 combined yards are the fifth highest all-purpose yards total in NFL history. In Week 17 of the 2009 season, versus the Indianapolis Colts, Jackson had a career day with 212 rushing yards and a receiving touchdown. In 2011, Jackson was having his best season to date, as the team's undisputed starting running back. Jackson had six 100-yard rushing games in the first ten weeks. During a Week Eleven loss to Miami, however, Jackson suffered a fractured fibula. Jackson was placed on injured reserve later in the week, and missed the remainder of the season.