Unsigned out of Division III Coe College in 2003, Fred Jackson took the hardest possible road to the NFL, starring in indoor football and grinding through NFL Europe with the Rhein Fire before finally catching on with the Buffalo Bills' practice squad. Making his NFL debut as a 26-year-old rookie in 2007, Jackson defied conventional career arcs to become one of the most productive and beloved running backs in modern franchise history.

Jackson exhibited a composed running style, superior vision, and remarkable resilience in pass protection. Predominantly operating from single-back and I-formation formations, his paramount characteristic was his versatility; he maneuvered with a low center-of-gravity advantage between the tackles while functioning as a natural, highly dependable receiver and an assertive contributor on special teams.

Jackson solidified his legacy within the NFL during the 2009 season. Establishing himself as Buffalo's primary offensive contributor, he accumulated 1,062 rushing yards and undertook kick-return responsibilities, amassing 1,014 kickoff return yards. Consequently, he became the inaugural player in NFL history to achieve 1,000 rushing yards and 1,000 kickoff return yards within a single season. He concluded the year as the NFL's leading all-purpose yardage holder with an impressive total of 2,516 yards, thus earning the team's Most Valuable Player award.

Despite sharing backfields with players such as Marshawn Lynch and C.J. Spiller throughout his career, Jackson consistently exceeded expectations. He surpassed 1,000 yards from scrimmage on five occasions in Buffalo (2008, 2009, 2011, 2013, 2014). His most productive rushing period occurred in 2011, when he averaged 5.5 yards per carry and accumulated 934 rushing yards over just 10 games before a leg injury prematurely ended what was on track to be an All-Pro season.

After eight seasons with the Bills (2007–2014) and a final year in Seattle, Jackson retired, having played 122 games (61 starts) with 5,746 rushing yards, 2,897 receiving yards, 1,014 return yards, and 39 touchdowns.