Philip Rivers makes his second start for the Indianapolis Colts when the ageless arm faces the visiting San Francisco 49ers on Monday Night Football in Week 16.
Rivers came out of a five-year retirement to bail Indianapolis out of its QB quandary and performed better than expected in a tight loss to Seattle last Sunday. Oddsmakers have Rivers and the Colts as home underdogs for MNF.
My early 49ers vs. Colts predictions and NFL picks believe there's value on the home pup for Monday, December 22.
49ers vs Colts predictions
Here are our early thoughts on the spread and total for this week’s game. We will have a full game preview (with a best bet and SGP) later in the week.
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Early MNF spread pick: Indianapolis Colts +5.5
Call it a Christmas miracle, but 44-year-old Philip Rivers walked away from his Week 15 start against Seattle intact.
The Indianapolis Colts' offensive line kept the Seahawks’ vaunted pass rush at bay, and Rivers managed to run this offense well enough for the Colts to cover as 13-point underdogs.
Indy comes home after two straight road games and faces a much softer opponent, at least in terms of defense. The Colts clashed with top stop units from Seattle, Houston, Jacksonville, and Kansas City on their current four-game losing skid, but the San Francisco 49ers aren’t as stingy.
San Francisco sits in the bottom third of most defensive metrics, especially when it comes to stopping the run. The 49ers are 26th in PFF’s run defense rating, 26th in Run Defense DVOA at FTN, and 31st in opponent success rate per run.
With Rivers under center, Indianapolis ran on 52% of its offensive snaps and employed a slow pace with the replacement QB still learning the playbook. Running back Jonathan Taylor rushed 25 times, tying his second-most carries on the season.
If the Colts can slow-roll the Niners' defense on the ground and dominate possession, I could see them covering this spread.
Early MNF total pick: Under 46.5
The last thing the Colts want is for this game to turn into a shootout, putting Rivers in a bad position.
While he has another week to get up to speed with the playbook and his receivers, it was clear Rivers has lost a lot of pop with his throws and isn’t able to escape pressure. His longest completion was a 17-yard strike, and his 4.4 yards per attempt was second lowest for Week 15.
The 49ers' defense tries to keep everything in front of it. While San Francisco doesn't bring much pressure, it uses a high rate of zone and tackles extremely well. The Niners don't allow explosive plays and might not have to worry about those with Rivers' old-ass arm out there.
San Francisco has hung some sizeable scores in recent outings but has also faced some bad and broken teams. The 49ers torched the Tennessee Titans for 37 points on Sunday and gave up 14 points in garbage time to go well Over their closing total of 45 points in Week 15.
The Colts are still a solid defensive team, sitting around the Top 10 in many metrics, including run stop. Indianapolis is No. 4 in EPA allowed per run, 13th in Run Defense DVOA, and tops in yards allowed per carry.
That could throw a wrench in the Niners’ run-centric playbook that leans on RB Christian McCaffrey to spark the play-action passing game. Quarterback Brock Purdy hasn’t been the most explosive passer in an injury-plagued 2025 and faces a man-heavy coverage from the Colts, a scheme he’s struggled against throughout his career.
This total is seeing the vig on Over 46.5 climb to -115, which could mean a move to the key number of 47 points is coming. If you like the Under, wait and see if this total ticks up later in the week.
49ers vs Colts odds
- 49ers vs. Colts spread: Colts +5.5
- 49ers vs. Colts moneyline: 49ers -250, Colts +205
- 49ers vs. Colts Over/Under: 46.5
How to watch 49ers vs Colts
- 49ers vs. Colts matchup
- Date: Monday, December 22, 2025, 8:15 p.m. ET
- City: Indianapolis, IN
- Venue: Lucas Oil Stadium
- TV: ESPN/ABC
Odds are correct at the time of publishing and are subject to change.
Not intended for use in MA.
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