49ers vs Colts Picks & Closing Odds

• The Indianapolis Colts are 4.5-point home underdogs vs the San Francisco 49ers
• San Francisco clinched a playoff berth as the Lions lost to the Steelers
• Keep reading for updated 49ers vs Colts closing odds, predictions and picks for MNF

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Week 16 results have pushed the San Francisco 49ers (10-4, 6-2 away) into the playoff bracket in the NFC. 

Their opponent Monday Night, the Indianapolis Colts (8-6, 6-1 home) will be required to do the heavy lifting on their own if they want to be part of the playoff party in the AFC.

Even as the more desperate side, the books have Indy as the home underdog in the Monday Night Football odds.

Kickoff is set for 8:15pm ET from Lucas Oil Stadium in Indianapolis, with ABC and ESPN carrying the broadcast.

49ers vs Colts Picks & Prediction

• Colts +4.5 (-105 at FanDuel)

A team that was once 8-2 and destined for a Wild Card berth at least, Indianapolis’ season has slid off the rails as they’ve lost their starting QB Daniel Jones, dropping four straight.

The fourth and most recent loss, to Seattle, had 44-year-old Philip Rivers off the scrap heap and into the starting lineup, as the Colts’ QB room was doubling as a MASH unit.

Rivers did about as much as he could do, throwing for 120 yards and a TD, while tossing an interception to seal the game as he was trying to drive the Colts down the field, in an 18-16 loss to the Seahawks.

With three games to go, the Colts still control their own destiny. Win out, and they assure a spot in the playoffs. 

San Francisco is the first pillar in this three-step journey, then division W’s against the Jacksonville Jaguars and on the road in Week 18 against the Houston Texans.

Indy has shown a lot of fight, keeping three of the four losses inside of a four-point differential, but they are struggling to get over the hump. 

A Jonathan Taylor breakout would be a monster help, as the Colts star has been held to less than 90 yards rushing in each of the four losses. San Fran is only allowing 106.1 yards on the ground this season.

Where they can make some hay (potentially) is in the pass game, where the Niners are Bottom 10 in yards allowed, and last in the NFL with just 16 sacks — the only team in the league yet to crack the 20-sack plateau.

The Niners have won four in a row and are 4-0-0 against the spread in those games, but I think it’s human nature to take a breath after going all out to get into the end-of-year-tourney. 

They’re also down WR Ricky Pearsall (knee/ankle), CB Renardo Green (neck), DE Yetur Gross-Matos and LB Nick Martin (concussion). Perhaps more backups will see action too.

The Colts are the more desperate team, and should be able to keep this close, if not win outright to stay alive.

49ers vs Colts Closing Lines

As we close in to kickoff, the Colts find themselves as 5-point underdogs at BetMGM, while the best odds to win outright come from bet365, at +200. While there, you can also find the Niners as -4.5 favorites against the spread.

Over at DraftKings, they have San Francisco to win at a short -230.

For those betting the Over, bet365 has the total at 46 points, while Under bettors can grab an extra half point from the folks at FanDuel.

The interactive table above will automatically update as the NFL betting odds move over the course of the day.

SF 49ers vs IND Colts Line Movement

Just over a week ago, you could have found the Colts as 7-point underdogs against the Niners, but there’s been a lot of movement. With Pittsburgh doing Frisco a favor and topping Detroit, the line has moved to a low of 4.5 points.

The moneyline has shifted as well, with San Fran down to around -265 odds after living in the -300 range. It hasn’t been as dramatic a shift for the Colts, who still find themselves around +200 ‘dogs, after sitting in the +220-+230 area.

There hasn’t been much movement around the total, where it’s stayed primarily at 46.5 points, with a few half-point fluctuations in either direction.

The public loves Over 46 in 49ers vs Colts tonight 👀

The latest Monday Night Football betting splits 👇 pic.twitter.com/IJTj6CG80P

— SportsBettingDime (@SBD) December 22, 2025

The Niners still have an outside shot at the NFC West crown, and I guess that’s what the NFL public betting percentages are banking on, with a whopping 86% of bets and 84% of the money on San Francisco to win outright. 

It’s still skewed in the spread to the Niners, who have 64% of the wagers and 66% of the money on covering a 4.5-point spread. 

The total is also leaning to the Over, with 74% of the bets and 62% of the money taking the Over at 46 points.

SF vs IND Betting Trends

• The Colts are 6-1 at home this year, and are 4-2-1 ATS in those seven games
• The 49ers are 5-0-0 against the spread as road favorites this season
• San Francisco is 5-0-0 ATS in their last five games overall as favorites, while Indianapolis is 4-1 ATS as an underdog this season 
• The Colts have lost 11 straight games to NFC opponents as an underdog