Nelson was born in Melbourne, Florida in 1983. He attended Palm Bay High School in Melbourne, and was a standout high school football player for the Palm Bay Pirates. He was teammates with Joe Cohen and Xavier Carter. Nelson was a two-time first-team All-State honoree, and helped lead Palm Bay to win Florida Class 4A state championship as a safety and return specialist in 2002. As a senior, Nelson averaged forty-five yards per punt return and 26.8 yards per kickoff return, totaling a state record 1,531 return yards. In 2007, four years after he graduated from high school, the Florida High School Athletic Association (FHSAA) named Nelson to its "All-Century Team," recognizing him as one of the thirty-three greatest Florida high school football players of the last 100 years. He was taught how to play football by Rob Robbins.
Nelson accepted an athletic scholarship to play for coach Urban Meyer's Florida Gators football team in 2005 and 2006. Nelson was an immediate sophomore starter for the Gators at free safety in 2005. Nelson started in four games, and registered forty-six tackles, with four sacks, and forced a fumble. Against Georgia, Nelson recorded a career-high seven tackles. He also totaled seven tackles against Vanderbilt and Florida State.
In his junior year, which would end up being his last as a Gator, Nelson was selected as a member of the team's Leadership Committee, which was only one small highlight of his 2006 campaign. The Gators ended up going to the BCS National Championship Game and defeated the Ohio State Buckeyes, while Nelson recorded fifty-one tackles, five pass breakups and six interceptions. Two of his interceptions were against the Tennessee Volunteers, and he returned another for a seventy-yard touchdown against the Alabama Crimson Tide. Nelson was a first-team All-SEC selection and a consensus first-team All-American, and he was chosen by his Gators teammates as the team's most valuable player.
In 2006, he was part a defense that helped the Gators win their first SEC title in six years and their first national championship in ten years. While also gaining him the moniker "The Eraser" for his strong defensive play throughout the season as well as the "battle for the SEC" game against LSU.
Nelson was selected by the Jacksonville Jaguars in the first round (twenty-first pick overall) of the 2007 NFL Draft. After the departure of free safety Deon Grant as a free agent and the release of strong safetyDonovin Darius, Nelson led the Jaguars with seven tackles in their season opener against the Tennessee Titans in his first NFL game. He also sacked Tennessee quarterback Vince Young, causing a forced fumble. He ended the year with sixty-three tackles, one sack, one forced fumble and five interceptions.
On September 4, 2010 he was traded to the Cincinnati Bengals. In return, the Jaguars received cornerback David Jones. During the 2011 season, Nelson led the Bengals with four interceptions. He was third on the team in tackles (102) and tied for second on the team in forced fumbles (two), including one that fellow Gator alumnus Carlos Dunlap returned for a touchdown against the Indianapolis Colts. Nelson returned his first interception of the 2011 season 75 yards for a touchdown against the Seattle Seahawks—the fifth-longest interception return in Bengals history.
Following the 2011 season, Nelson became a free agent. The Bengals re-signed him on March 18. 2012.
Nelson's sister, Lynisha, is a basketball player for Florida Tech and his brother, Michael Nelson, is a teacher in the Miami-Dade public school system. Nelson's mother, Mary Lakes, who had breast cancer for several years, died on December 21, 2006, weeks before the 2007 BCS National Championship Game. As a result, Nelson was excused from participating in the daily media briefings leading up to the game.
On Sept. 30th 2007, a car driven by Justin Glass with passengers Corey Smith and Randall Cason was approached by two individuals one of whom opened fire on the car. Smith received a gunshot wound to the back of his head and was in a coma for two days while Glass was shot in the arm. Cason who was unhurt in the incident initially identified Reggie Nelson as the man accompanying the shooter, identified as Aaron Hernandez. Cason later rescinded his identification of Aaron Hernandez as the shooter and Reggie Nelson as the accomplice. No charges from this incident were ever brought against either Hernandez or Nelson.