Hamilton played baseball growing up in North Carolina. He was the first overall pick in the 1999 Major League Baseball Draft by the Tampa Bay Devil Rays. He was considered a blue chip prospect until injuries and a drug addiction derailed his career in 2001. Prior to the 2007 season, Hamilton was selected by the Chicago Cubs (picking for the Cincinnati Reds) in the Rule 5 Draft. He made his MLB debut in 2007 with the Reds and had a successful rookie season. During the off-season he was traded to the Texas Rangers for Edinson Volquez and Daniel Ray Herrera.
After his torrid start to the 2008 season, Hamilton was named to the American League All Star team. He also participated in the Home Run Derby, where he hit a record 28 home runs in the opening round and finished with 35 home runs, which was second-most all-time in derby history.