Luck engineered a 14-play drive down the stretch, capped by Donald Brown's short-yardage TD run as the Colts (4-1) notched a third straight win and knocked the Seahawks from the ranks of the unbeaten.
Darius Butler sealed with victory with an interception of Seattle's Russell Wilson.
Luck finished with 229 yards -- 140 of them going to T.Y. Hilton, who made five catches and scored twice in the win.
Wilson provided 312 yards of total offense for Seattle (4-1), whose nine-game regular-season winning streak came to an end.
The signal-caller and Marshawn Lynch each rolled up 102 rushing yards for the Seahawks.