Selected 28th overall in the first round of the 2004 NFL Draft from Ohio State, Chris Gamble joined the Carolina Panthers as an athletic and versatile defensive back. Throughout his nine-season career in the NFL, Gamble remained with the Panthers, positioning himself as the steadfast cornerstone of the secondary and developing into the franchise’s most prolific performer in terms of takeaways.

Gamble exhibited elongated arms, expressive hips, and hands reminiscent of a receiver, developed throughout his dual-role collegiate career as a Buckeye. Serving as Carolina’s principal perimeter cornerback, he concentrated on press-man and tight zone coverage, employing meticulous footwork to shadow speed receivers along the boundary. His gentle hands and innate instincts enabled him to deceive opposing quarterbacks, converting narrow passing opportunities into immediate turnovers.

Gamble made an immediate impact during his rookie season in 2004, starting all 16 games and intercepting 6 passes—achievements that earned him PFWA All-Rookie Team recognition and ranked him among the league leaders in interceptions. He elevated his performance further in 2005, recording a career-high 7 interceptions and returning one for 61 yards for a touchdown, thereby contributing significantly to the Panthers' advancement to the NFC Championship Game.

Throughout the subsequent seven seasons, Gamble maintained his position as the quintessential reliable presence on the periphery. He achieved multiple-interception campaigns in six distinct seasons and consistently ranked among the leading defensive backs in passes defended, regularly neutralizing the opponent's primary target. His accumulation of 27 career interceptions surpassed that of Eric Davis, thereby establishing the Carolina Panthers' all-time franchise record.

After four games in 2012, a shoulder injury ended Gamble's season and placed him on injured reserve. The Panthers released him in March 2013, and he chose to retire instead of joining another team. Over his career, Gamble recorded 508 tackles, 96 pass deflections, 27 interceptions, and 2 defensive touchdowns.