The Week 3 AFC South clash between the Indianapolis Colts and the Tennessee Titans on September 21, 2025, is shaping up to be a physical, grind-it-out matchup that will pit two teams still searching for long-term consistency but eager to gain divisional ground in the early part of the season, and given the recent history of close games between these rivals, it should once again come down to execution in the trenches and which young quarterback can make plays in critical moments. For Indianapolis, the development of Anthony Richardson has been the story of the season, as his rare athleticism and steadily improving accuracy give the Colts a dynamic presence at the quarterback position that opponents must account for on every snap, and pairing that with the punishing running style of Jonathan Taylor provides a foundation that can wear down even the most disciplined defenses. Head coach Shane Steichen has crafted a scheme that maximizes Richardson’s skill set, emphasizing quick reads, designed runs, and play-action opportunities that open up passing lanes for Michael Pittman Jr. and a growing stable of young wideouts, making the Colts far more unpredictable than they have been in recent years. On the other side, Tennessee has committed to retooling without abandoning its identity, and though Derrick Henry is no longer the centerpiece, Tyjae Spears has stepped in with explosiveness and versatility, giving the Titans a running back capable of carrying the load while also contributing in the passing game, something that could be critical in keeping Will Levis comfortable in the pocket.

Levis remains an evolving piece of the puzzle, with flashes of arm strength and mobility offset at times by questionable decision-making, and this game against an aggressive Indianapolis defensive front led by DeForest Buckner and Shaquille Leonard will be a significant test of his poise and progress. The Titans’ passing attack has leaned on DeAndre Hopkins’ veteran savvy, but Tennessee needs more consistency from its younger receivers to complement Hopkins and give Levis outlets when the Colts collapse the pocket, and whether the offensive line can provide stability against Indy’s pass rush may determine how effectively Tennessee can move the ball. Defensively, Tennessee continues to lean on Jeffery Simmons and Harold Landry to set the tone up front, but containing Richardson outside the pocket is a far greater challenge than they are accustomed to, and if they allow him to extend drives with his legs, they risk being worn down by long, punishing possessions. Meanwhile, Indianapolis’ defense must stay disciplined against play-action and the threat of Spears, who has shown the ability to make defenses pay when they overcommit, and turnovers could easily become the deciding factor in what is expected to be a low-scoring, possession-heavy battle. From a betting perspective, this series has often favored the underdog, with spreads rarely being covered by wide margins, and the totals tend to trend under given both teams’ run-heavy approach, which eats up clock and limits possessions. This game will be a true measuring stick for where both franchises stand in 2025: the Colts seeking to prove that their young quarterback and power run game can sustain playoff-level success, and the Titans fighting to show that their new identity still makes them a contender in one of football’s most balanced divisions, setting the stage for a bruising contest that could be decided by a single big play late in the fourth quarter.