Unable to snatch a winnable game, the Chargers made fewer big plays than the Colts, who dealt San Diego a 26-22 defeat on Sunday at Lucas Oil Stadium.
The Chargers fell to 1-2 for the third time in four seasons under coach Mike McCoy.
In addition, the Chargers lost linebacker Manti Te'o to an Achilles injury and saw his impressive replacement, rookie Jatavis Brown, sit out the fourth quarter with an apparent ailment.
The Chargers, imprecise in the red zone, settled for too many field goals, but defensive end Caraun Reid's 61-yard scoring return with a fumble caused by Brown led to a 13-13 tie at halftime.
The game's No. 1 surprise was the big performance of Colts wide receiver T.Y. Hilton against Chargers cornerback Jason Verrett.
Verrett, who was banged up in the second half when a Colts player drilled him as he collected a muffed punt by Travis Benjamin, looked out of sync for most of the game.
Hilton had five catches against Verrett, including a 63-yard, decisive touchdown in which he got past Verrett and two safeties to move the Colts ahead, 26-22, with 1:17 left.
The quick and fast Hilton, who was listed as questionable this week with a knee injury, also had catches of 32 and 24 yards against Verrett. And he drew two penalties from the 2015 Pro Bowl alternate, whom Chargers coordinator John Pagano described this week as the NFL's best cornerback.
The Chargers saw their bid for a comeback victory end when Colts safety Clayton Geathers, coming from behind, knocked the ball from rookie Hunter Henry near midfield with 1:02 to play.
The Chargers overcame deficits of 10-0 and 13-7 to take a 22-20 lead in the third quarter.
A blocked one-point kick by Antonio Cromartie, a former Chargers standout, added to San Diego's challenges.
Philip Rivers threw for 330 yards, and Melvin Gordon ran one yard for a touchdown, the offense's only TD.
The Chargers will face the Saints next Sunday at Qualcomm Stadium.
The Colts (1-2) snapped a three-game losing streak against San Diego.
