After a tough, outright loss to the Seahawks last week, Philip Rivers makes his home debut for the Indianapolis Colts on Monday night.
Indianapolis will be searching for a spark as a near-touchdown home underdog against a San Francisco offense that’s finally back to full health and capable of putting pressure on this defense from the opening drive.
My 49ers vs. Colts predictions and NFL picks believe both offenses can put up points indoors on Monday, December 22.
49ers vs Colts prediction
49ers vs Colts best bet: Over 46.5 (-110)
This is a spot where context matters more than box scores, and it points clearly toward the Over.
The game shifts indoors, Philip Rivers gets another week to settle into this offense, and he’s no longer dealing with the chaos of Lumen Field. On the other side, the San Francisco 49ers are finally healthy on offense and could be one of the strongest units down the stretch.
THE BLITZ projects this total at 52.1 points, and there’s nothing about the Indianapolis Colts’ pace of play with Rivers under center that suggests they’re slowing games down compared to their season averages.
Last week’s stat line may look modest at first glance, but 120 yards on 27 attempts still included eight throws of 10-plus yards and nine targets to running backs. That usage hints at a more aggressive approach moving forward, something Shane Steichen reinforced by noting that game plans will vary week to week.
San Francisco’s defense just allowed 24 points and 6.2 yards per play to Tennessee, and Brock Purdy looked sharp coming out of the bye. This team is also 6-3-1 to the Over at home or indoors, where offensive efficiency jumps.
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49ers vs Colts MNF same-game parlay
The Colts will have more confidence passing the ball and might be forced to after an easy week vs. Seattle, where they played in a neutral game script from start to finish.
Rivers threw a lot of balls at or behind the line of scrimmage, as RB targets accounted for nine throws. Those might move downfield on Monday, and it was Ty Warren who led all Colts pass catchers in targets last week with six.
More aggressive passing means more yards for the grandpa, and even Cam Ward moved the ball vs. this 49ers defense last week.
49ers vs Colts SGP
- Philip Rivers Over 163.5 passing yards
- Tyler Warren Over 4.5 receptions
- Over 46.5
Our big-ticket SGP: MNF Shootout
There are some great Indy TD prices as Rivers has a passing TD total of 0.5. Let's stay on the Warren train and get the TE for a TD after a team-high in targets last week, and hopefully fewer balls going to RBs.
George Kittle will not be stopped, especially with a QB who looked past his turf toe injury last week. He has five TDs over his last seven games and is coming off a season-high 88 yards last week.
Indy might keep pace for a bit, but the 49ers' offense might be in its best form of the season.
49ers vs Colts SGP
- Tyler Warren anytime touchdown
- George Kittle anytime touchdown
- Over 46.5
- 49ers -5.5
49ers vs Colts odds
- Spread: 49ers -5.5 | Colts +5.5
- Moneyline: 49ers -270 | Colts +220
- Over/Under: Over 46.5 | Under 46.5
49ers vs Colts betting trend to know
The 49ers have gone Under the total in just three of their 10 games at home or indoors this season. Find more NFL betting trends for 49ers vs. Colts.
How to watch 49ers vs Colts
| Location | Lucas Oil Stadium, Indianapolis, IN |
| Date | Monday, December 22, 2025 |
| Kickoff | 8:15 p.m. ET |
| TV | ESPN or ABC |
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