At Southern, he concentrated on his academics, not playing football until his junior year. Eventually, after being encouraged by his old high school teammate Maurice Hurst, he decided to join the team as a walk-on. He started out playing mostly on special teams, but made the starting lineup in the 5th game. In the following season, Williams was named to the All-Southwestern Athletic Conference team after leading the conference with seven interceptions. In 1990, Williams stayed on the team as a graduate student and fifth year senior in order to improve his draft status. He made the ALL SAC team again and tied the Division I-AA, (now known as the NCAA Football Championship Subdivision) record for most interceptions with eleven.

Williams’ numbers impressed the then-Phoenix Cardinals enough that they selected him in the third round of the 1991 NFL Draft, Williams quickly established himself with an exceptional rookie season, tying the NFC lead for interceptions. In 1994, he led the NFL in interceptions with 9. By 1997, Williams had already notched four Pro Bowl appearances and had established himself as the Cardinals’ top cornerback, routinely covering the opponents’ lead receivers. In the 1998 season, Williams helped the Cardinals win their first playoff game since 1947 by intercepting two passes from Troy Aikman in a 20–7 win over the Dallas Cowboys, and added another interception in the Cardinals 41–21 loss in the divisional round. Despite playing mostly for bad teams (1998 was the only time he played on a winning team during his 10 years in Arizona), Williams was recognized as one of the best cornerbacks in the league, making six Pro Bowls in all as a Cardinal. He is regarded as one of the best defenders and players in Cardinals history, as well as one of the greatest shutdown corners of all time. In 2000, he tied an NFL record, held by Jack Tatum of the Oakland Raiders, by returning a fumble (caused by Mark Maddox) 104 yards for a touchdown in a game against the Washington Redskins.

In 2001, Williams was traded to the St. Louis Rams on draft day in exchange for picks in the second and fourth rounds. Due to roster concerns, Williams switched to free safety. As one of the leaders of a much-improved defense, Williams got a chance to play in the postseason for only the second time in his career. In the Rams divisional playoff game against the Green Bay Packers prior to the Super Bowl, He returned two interceptions from Packers quarterback Brett Favre for touchdowns and recovered a fumble. Then in the NFC title game, he intercepted a pass from Philadelphia Eagles quarterback Donovan McNabb, with 2 minutes left in regulation, clinching the game and ensuring the Rams’ berth in Super Bowl XXXVI. However, the Rams lost that game to the New England Patriots.

Williams was inducted into the Arizona Cardinals’ Ring of Honor during the 2008–2009 football season during halftime of the Monday Night Football game against the San Francisco 49ers November 10, 2008. On January 18, 2009, he was chosen to present the George Halas Trophy to the Arizona Cardinals after their victory in the NFC Championship game, resulting in the Cardinals first trip to the Super Bowl. He made his final appearance in a football videogame in NFL Street 2, which was released in 2004.

Williams was a finalist for the Pro Football Hall of Fame classes of 2012 and 2013 but did not get voted in on the final ballots both times. He was elected to the Pro Football Hall of Fame on February 1, 2014, and inducted on August 2.

On September 24, 2014, Williams was inducted into the St. Louis Sports Hall of Fame.