Week Three: September 21, 2008 at Lucas Oil Stadium in Indianapolis, Indiana.
The Jaguars' Fred Taylor and Maurice Jones-Drew each went over 100 yards rushing, while Peyton Manning tossed two interceptions (one returned for a touchdown) as Jacksonville hit a 51-yard game-winning field goal to win 23-21. The Colts have lost their first two regular season home games at their brand-new stadium.