San Francisco 49ers vs Indianapolis Colts Betting Trends

The Monday night football clash on December 22, 2025, between the San Francisco 49ers and Indianapolis Colts at Lucas Oil Stadium in Indianapolis, IN, presents an exciting betting opportunity in the NFL. This game features a compelling quarterback matchup with San Francisco's Brock Purdy starting, coming off a strong offensive season, against Indianapolis' Daniel Jones, who steps in amid injuries to key players like Anthony Richardson Sr., listed as out. The Colts have shown resilience but have struggled recently, going 3-7 in their last 10 games, while the 49ers boast a 7-3 record in their last 10, making them favorites with a -5.5 point spread at Caesars.

Examining the betting trends, San Francisco holds a slight edge in passing offense averaging 246.1 yards per game compared to Indianapolis at 229 yards, while the Colts defend well against the pass but face challenges against the 49ers' balanced attack. On the ground, the 49ers average 28.9 rushing attempts per game with 101.4 yards, slightly outperforming the Colts' 26.6 rush attempts and 128.5 yards. Defensively, Indianapolis has a strong pass rush with 2.57 sacks per game versus San Francisco's 1.57, which could disrupt the 49ers' passing rhythm.

Betting insights suggest the total points line is set at 46, reflecting expectations of a moderately high-scoring game. The Colts' recent games have mostly gone under similar totals, while the 49ers have seen a mix of over and under results, adding intrigue to the over/under bet. Additionally, the Colts' home record is solid at 6-1, contrasting with the 49ers' strong away record of 6-2, making this a clash of strong venue performances that bettors should consider.

This game will be broadcast on ESPN, giving fans and bettors a prime viewing experience. For those looking to dive deeper into the numbers and maximize their betting edge, Start your OddsTrader Turbo subscription offers detailed analytics and odds tracking. Placing your wager with a U.S. regulated sportsbook like Caesars, offering the best odds for this game, is a smart move.

In their last matchup on October 24, 2021, the Colts defeated the 49ers 30-18, covering the spread as a 3.5-point underdog, a historical note worth considering when examining the current betting trends.