He played college football for the Louisiana–Lafayette Ragin' Cajuns, and was selected by the Chicago Bears in the second round of the 2003 NFL draft.

Head coach Dick Jauron named Tillman the third cornerback on the depth chart to begin the regular season, behind R. W. McQuarters and Jerry Azumah.

He made six solo tackles and deflected a pass as the Bears defeated the Oakland Raiders 24–21 to earn their first victory of the season.

Tillman intercepted a pass by Lions' quarterback, that was originally intended for wide receiver Az-Zahir Hakim, and returned it for a 32-yard gain during the second quarter.

[19] Tillman completed his rookie campaign with a total of 83 combined tackles (76 solo), eight pass deflections, four interceptions, and one sack in 16 games and 13 starts.

[21] Head coach Lovie Smith named Tillman and R. W. McQuarters the starting cornerbacks to begin the 2004 NFL season.

On September 19, 2004, Tillman collected a season-high 11 combined tackles (nine solo) during a 21–10 victory at the Green Bay Packers in Week 2.

[22] He finished the 2004 NFL season with 39 combined tackles (32 solo), five pass deflections, and one forced fumble in eight games and seven starts.

On October 30, 2005, Tillman recorded seven combined tackles (six solo), deflected two passes, and returned an interception for his first career touchdown during a 19–13 overtime victory at the Detroit Lions in Week 8.

[23] On December 11, 2005, Tillman recorded eight combined tackles (five solo), deflected a pass, and made a season-high two forced fumbles during a 21–9 loss at the Pittsburgh Steelers in Week 14.

He finished the season with 93 combined tackles (82 solo), 11 pass deflections, five interceptions, four forced fumbles, one sack, and one touchdown in 15 games and 15 starts.

On January 15, 2006, Tillman started his first career playoff game and recorded six solo tackles and a pass deflection as the Bears lost 29–21 against the Carolina Panthers in the NFC Divisional Round.

[26] Many Bears' fans believe that Tillman should have been voted to the 2007 Pro Bowl, as he recorded more interceptions and tackles than DeAngelo Hall and Ronde Barber.

[28] On December 8, 2007, Tillman was nominated as finalist for the prestigious Walter Payton NFL Man of the Year Award, which recognizes players who have performed extensive charity work.

[30] During a Monday Night Football game against the Minnesota Vikings on December 28, 2009, Tillman collided with Bears safety Craig Steltz while attempting to tackle Visanthe Shiancoe.

[33] Tillman is tied with Donnell Woolford for the most interceptions by a cornerback in team history, trailing only safeties Gary Fencik and Richie Petitbon.

[34] On November 4, 2012, Tillman forced four fumbles against the Tennessee Titans offense, the most in a game by a single player in league history since the stat began being tracked in 1991.

[40] In the 2013 season opener against the Cincinnati Bengals, Tillman recorded two interceptions, the second time in his career he had two picks, after 2006 against the New England Patriots.

[42] However, on December 16, Bears head coach Marc Trestman reported that Tillman will miss the entire season, playoffs included.

[44] In February 2014, the NFL awarded Tillman the Walter Payton Man of the Year to acknowledge his charitable efforts and community outreach programs.

[58] Tillman's Cornerstone Foundation mission is to help improve the lives of critically and chronically ill children throughout Chicago.