The Texans struggled to move the ball downfield against the Colts, with quarterback Deshaun Watson held to 235 yards, one touchdown, and an interception on 29-of-49 passing.
"We had a lot of multi-play drives. Our red area has been horrendous for us the whole year. We had a lot of trips into the red area but we have not been able to score touchdowns down there, and that was the case today," O'Brien said, according to Michael David Smith of Pro Football Talk.
Watson and Co. were presented with an opportunity to score late in the second quarter with a fourth-and-1 on the Colts' 9-yard line, but the quarterback failed to connect with star receiver DeAndre Hopkins.
The Texans would eventually get on the board when Watson found Keke Coutee for a six-yard touchdown pass early in the fourth quarter, but it was too little, too late.
Watson completed just 45.2 percent of his passes from inside the 10-yard line this season.