 Head coach Norv Turner retained Weddle as the starter to begin the regular season, along with Steve Gregory.On November 28, 2010, Weddle recorded four solo tackles, a season-high two pass deflections, and returned an interception for a touchdown during a 36–14 victory at the Indianapolis Colts in Week 12.He returned an interception by quarterback Peyton Manning, that was intended for wide receiver Reggie Wayne, in the third quarter.