San Francisco 49ers vs. Indianapolis Colts Picks and Prediction for Monday, December 22, 2025
Use Code WWWC It’s an interconference matchup on the gridiron between a pair of teams looking to head into Christmas on a positive note in the Hoosier State as the San Francisco 49ers take on the Indianapolis Colts on Monday Night Football and we have you covered with our 49ers vs. Colts prediction. San Francisco dropped Tennessee 37-24 at home last Sunday in their previous contest, covering the line as a 12.5-point favorite. Indianapolis suffered an 18-16 road loss to the Seahawks on the road last Sunday, covering the line as a 13-point underdog, in their previous game. In the all-time regular season series between the teams, the Colts own a 27-18 advantage and have won the last five meetings, including a 30-18 road win in the most recent clash October 24, 2021. Read more about this 49ers vs. Colts prediction! Don’t get sacked this football season! Try our NFL Picks!
49ers Trying to Lock Down Playoff Spot
San Francisco ran their win streak to four games as they took down Tennessee in their previous contest. The 49ers improved to 10-4 on the year and stand third in the NFC West, 1.5 games behind the Seahawks for the top spot. They own the sixth seed in the NFC playoff picture. Against Tennessee, San Francisco took a 7-0 lead midway through the first quarter and never looked back. The 49ers were up 7-3 after the opening quarter, 17-10 at the half and 31-10 after three quarters en route to the win. San Francisco rolled up a 430-306 edge in total offense, picked up 28 first downs while allowing 18, controlled the clock by a 37:05 to 22:55 margin and committed the game’s lone turnover.
On the year, the 49ers are 4th in the league in passing as they average 246.1 yards per game through the air. San Francisco is 25th in the league in rushing offense as they pile up 101.4 yards per game on the ground this season. The 49ers are 11th in the league in scoring offense as they put up an average of 24.6 points per game. San Francisco is 11th in the league in scoring defense by allowing an average of 20.9 points per contest. Brock Purdy is 129 of 190 passing for 1,442 yards with 12 touchdowns and seven interceptions while getting sacked six times. He adds 87 yards and a score on the ground. Mac Jones (201 of 289, 2,151 yards, 13 TD, six INT, 63 rush yards) has stepped up with Purdy missing time. Christian McCaffrey leads the ground game with 259 carries for 922 yards and nine scores. Brian Robinson Jr. (81 carries, 349 yards, two TD) is the second back in the system. McCaffrey leads the team with 86 receptions for 820 yards and five scores this season. Jauan Jennings (44 catches, 495 yards, seven TD), tight end Jake Tonges (26 grabs, 226 yards, three TD), George Kittle (45 catches, 484 yards, six TD), Kendrick Bourne (33 catches, 499 yards) and Ricky Pearsall (31 receptions, 443 yards) are all over 200 receiving yards on the season. Jake Moody was two of two on extra point attempts and one of three on field goal attempts with a long of 32 this season before being cut after the opener. Matt Gay is four of four on extra point attempts and four of four on field goal attempts with a long of 47. Eddy Piniero is 22 of 26 on extra points and 25 of 25 on field goals with a long of 59 on the year.
Key Injuries for 49ers:
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- Cornerback Renardo Green (neck) is out.
- Wide receiver Ricky Pearsall (knee/ankle) is out.
- Quarterback Kurtis Rourke (knee) is out.
- Defensive lineman Yetur Gross-Matos (hamstring) is questionable.
Indianapolis Hoping to Reverse Recent Meltdown
Indianapolis has crumbled down the stretch, suffering their fourth straight loss as they were defeated by Seattle on the road in their previous contest. The Colts dropped to 8-6 on the year and stand third in the AFC South, two games behind Jacksonville for the top spot. They stood one game behind Houston for the final wild card spot in the AFC. Against Seattle, Indianapolis kept the Seahawks out of the end zone in the contest yet still managed to end up falling short. The Colts led 13-6 at the half and 13-9 after three quarters, trailed 15-13 in the fourth quarter and took a 16-15 edge with 47 seconds remaining on a Blake Grupe 60-yard field goal. Their defense couldn’t make the stop they needed though as Seattle booted a 56-yard field goal with 18 seconds remaining to send them to defeat. Indianapolis was outgained 314-220 in total offense, gave up 15 first downs while recording 14 and committed the game’s lone turnover. Those numbers more than offset the Colts’ 31:05 to 28:55 margin in time of possession in the game.
On the year, the Colts are 9th in the league in passing offense with an average of 229 yards per game through the air while they are tied for 6th in rushing offense with 128.5 yards per contest on the ground. Indianapolis is 6th in the league in scoring offense with 28 points per game while they stand 12th in scoring defense by allowing 21.6 points per contest. Daniel Jones is 261 of 384 passing for 3,101 yards with 19 touchdowns and eight interceptions while adding 164 yards and five scores on the ground. Riley Leonard (18 of 31, 145 yards, INT, six rush yards, TD), Philip Rivers (18 of 27, 120 yards, TD, INT) and Anthony Richardson Sr. (one of two, nine yards) have seen action with Rivers the current starter. Jonathan Taylor leads the team with 272 carries for 1,443 yards plus 16 scores on the ground this season. DJ Giddens (18 carries, 66 yards) is next in line. Michael Pittman Jr. is leading the team with 72 receptions for 725 yards plus seven scores on the year. Josh Downs (47 catches, 406 yards, four TD), Alec Pierce (39 receptions, 785 yards, two TD), Taylor (38 receptions, 318 yards, two TD), Tyler Warren (63 grabs, 718 yards, four TD) are all reliable targets this season. Spencer Shrader hit all 14 extra point attempts and 13 of 14 field goal attempts with a long of 52 on the year. Michael Badgley is 18 of 21 on extra point attempts and 10 of 11 on field goal attempts with a long of 53 this season. Blake Grupe is two of two on extra points and five of five on field goal attempts with a long of 60 this year.
Key Injuries for Colts:
- Cornerback Sauce Gardner (calf) is out.
- Wide receiver Anthony Gould (foot) is out.
- Quarterback Anthony Richardson Sr. (eye) is out.
- Safety Daniel Scott (knee) is out.
- Defensive tackle DeForest Buckner (neck) is questionable.
- Tackle Bernhard Raimann (elbow) is questionable.
49ers vs. Colts Pick
Spread Pick for 49ers vs. Colts
- 49ers -5 (4 units)
Indianapolis has struggled offensively of late, dropping four straight games and have scored 20 points or less in five of their last six contests. The Colts had to turn to Rivers after Jones went down with his Achilles injury and he looked like a guy who hadn’t played since 2020. Indianapolis hung tough against Seattle but their offense has flatlined. They now face another tough defense in San Francisco and the 49ers have momentum going for them at this point. Indianapolis is reeling at the moment and the 49ers are playing solid football. With the quarterback situation in flux for the Colts, you have to fade them here. Take San Francisco in this contest as they win a fifth straight game.
Over/Under Pick for 49ers vs. Colts
- Under 46.5 (4 units)
San Francisco has seen the over post an 8-5-1 mark on the year entering this game. On the road this season, the 49ers have seen the over post a 5-2-1 mark, though they did stay under the total in their most recent road contest against Cleveland. Indianapolis has split their 14 games on the year in relation to the total this season. The Colts have gone over the total in four of their seven games at home this year. They have stayed under the number in four of their previous six games entering this one. With the Colts struggling to generate much in the way of offense of late, this game winds up falling short of the total.
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