Woodson starred at football at Purdue University, winning All Big Ten and All American honors in 1985 and 1986. Woodson also starred in track, qualifying for the 1984 Olympic Trials. In 1987, Woodson was drafted by the Pittsburgh Steelers. He returned punts and played defensive back for Pittsburgh through the 1996 season. A highlight came in 1995, when Woodson became the first player to return from reconstructive knee surgery in the same season. That year he tore his Anterior Cruciate Ligament in the first game and returned to play in the Super Bowl XXX between the Steelers and Dallas Cowboys just 19 weeks later.

Woodson's career took a somewhat nomadic turn after free agency from Pittsburgh. Although he has remained to raise his family in Pittsburgh he has hopped between three additional franchises. Woodson signed with San Francisco for the 1997 season, Baltimore for the years 1998 to 2001 (where he won a Super Bowl), and the Oakland Raiders for 2002 and 2003 (where he appeared in his third Super Bowl). In 2001, after fourteen seasons in the league, Woodson finally got to play on the winning side in Super Bowl XXXV.

He officially retired in 2004. A consummate professional, Woodson is among the NFL's all time leaders in games played as a defensive back and interceptions. In his 17 NFL seasons, Woodson recorded 71 interceptions, 1,483 interception return yards, 32 fumble recoveries, 137 fumble return yards, 2,362 punt return yards, and 15 touchdowns (12 interception returns, 1 fumble return, 2 punt returns.) 

For his excellence on the field, Woodson has been named to the Pro Bowl eleven times. Woodson was named 1993's NFL Defensive Player of the Year by the Associated Press. In 1994, he was named to the NFL's 75th Anniversary Team. The Sporting News and College Football News have also honored him as one of the 100 greatest players of the 20th century.

In 2007, Woodson began commentating for the NFL Network. In February 2011, Woodson was hired by the Oakland Raiders to be their cornerbacks coach.