San Francisco 49ers vs Indianapolis Colts Prediction, Odds and Picks for Monday, 12/22/25

Phillip Rivers will return to Monday Night Football in just his second week back and needless to say, this feels like it’ll be a highly entertaining watch. In his first start he played well, far above expectations considering he’s a 44-year old quarterback who hasn’t been in the league for five years. Rivers also had his first appearance against one of the toughest defenses in the NFL, a Seahawks’ group that ranks top-5 in EPA per pass. Shane Steichen gave Rivers an easy-to-follow gameplan which incorporated many short, simple throws to get him back in the fold, and the veteran went 18-27 for 120 yards for one touchdown and one interception. Of course that wasn’t a particularly impressive performance, but Rivers never looked rattled or out of his comfort zone. In fact he seemed to have command over the offense, calling audibles and vocally leading his comrades with the same ferocity he was known for in San Diego.

The Colts’ defense played very well last weekend, limiting the home-team Seahawks, one of the most potent offenses, to just 314 yards. A unit that ranks 11th in total defensive EPA, Indianapolis has its flaws on that side of the ball, particularly against opposing quarterbacks (ranked 14th in EPA per pass and permitting 7.1 yards per pass, 16th). We expect them to show their best form on Monday night, along with the rest of their squad, since their chances at a postseason run lie in the balance.

The 49ers won in Week 15 in what was an easy-breezy win for the most part, although they allowed the hapless Titans to eventually score 24 points. San Francisco sprinted out to a 31-10 lead and played more casually after that. They barely covered the spread (-12.5), but a late field goal with just two minutes left helped secure the needed margin. In general the 49ers are an average team with good leadership and mostly good quarterback play (4th in completion percentage, 10th in yards per pass), and they’re also fighting for their postseason spot in a crowded NFC West.

If the playoffs started today, the Niners would be in. They also have a favorable schedule remaining to round up their season, with two home games incoming in Weeks 17 and 18. The Colts are the more desperate team, since they’re currently outside the playoff picture, meaning every game qualifies as a must-win. They also have a difficult remaining schedule against two more AFC South opponents. We like the Colts to give it their all and to throw the kitchen sink at the Niners, plain and simple.

San Francisco 49ers vs Indianapolis Colts prediction: Colts +6 (-110) available at time of publishing. Playable at that number.

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