Indianapolis Colts vs Tennessee Titans Prediction, Odds and Picks for Today, 09/21/25

The lone undefeated team in the AFC South is the Indianapolis Colts at 2-0, as they hit the road for the first time this season on Sunday to face the winless Tennessee Titans. The Colts rolled past the Dolphins in the season opener, 33-8 as QB Daniel Jones threw for 272 yards and was responsible for 3 touchdowns (1 passing and 2 rushing). Indianapolis had to work for its 2nd victory, defeating Denver in the final seconds on a 45-yard game-winning field goal, 29-28. Jones tossed 316 yards through the air, while RB Jonathan Taylor amassed 165 yards on the ground for the Colts.

The Titans are seeking their first win under rookie QB Cam Ward following a pair of losses to the Broncos and Rams. To be fair, Tennessee hung around in both games, but it has scored only 1 touchdown so far. In Sunday’s home defeat to Los Angeles, Ward threw his first career TD pass as the Titans led the Rams, 16-13, late in the 3rd quarter. LA outscored Tennessee 20-3 the rest of the way for the 33-19 victory and cover as 5.5-point road favorites. Ward has failed to reach 200 passing yards in each of his first 2 pro starts. Following 112 passing yards in his debut at Denver, he slightly improved against the Rams with 175 yards. The more telling number is his completion percentage improvement, going from 42.9% against the Broncos to 57.6% against the Rams.

Last season, the Colts swept the Titans, extending Indianapolis’ winning streak over Tennessee to 4 games since the start of 2023. Indianapolis won all 4 games by 8 points or less, including back-to-back 3-point victories in Nashville. In 2024, Indianapolis compiled a 3-6 road record, including a 1-2 straight-up and 0-3 against the spread mark as a favorite. The Titans posted a 4-2-1 ATS mark as a home underdog in head coach Brian Callahan’s first season before losing last week.

Here’s an interesting angle to take on the Titans heading into this week — since 2013, underdogs that are 0-2 have put together an incredible 44-24 ATS (64.7%) mark. Let’s look at the Titans here to cash as a home underdog and at least keep this one within a field goal.

Colts vs Titans prediction: Titans +3.5 (-110) available at time of publishing. Playable to 3.

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