San Francisco 49ers vs Indianapolis Colts Prediction, 12/22/2025 NFL Picks, Best Bets & Odds Week 16

Game: San Francisco 49ers vs Indianapolis Colts

Date: Monday, December 22, 2025

Location: Lucas Oil Stadium in Indianapolis, IN

TV: ESPN

Odds-Point Spread: Colts (+6)

Total-Over-Under: 46.5

Lucas Oil Stadium is the location where the Indianapolis Colts (8-6) will meet the San Francisco 49ers (10-4) on Monday. Indianapolis is 6-point dogs from Vegas oddsmakers. The total is set at 46.5.

The San Francisco 49ers head into this game 10-4 over the course of this year. The last time they stepped on the gridiron, the 49ers went up against the Tennessee Titans and went home with a win by a final score of 37-24. Brock Purdy finished 23-30 with 295 yds passing and 3 TDs. He had a QB rating of 140.3 and walked away from the game without throwing an interception. Christian McCaffrey was the rushing leader for the 49ers with 22 carries for 73 yards (3.3 yds per carry). George Kittle averaged 11.0 yds per catch by totaling 88 yards on 8 catches. The San Francisco 49ers ran the ball 38 times and accumulated 138 yards, which came out to an average of 3.6 yards per carry. In all, they tallied 68 plays which gave them 430 yds. San Francisco surrendered 18 completions on 29 tries for 170 yards, and a completion rate of 62.1%. Against the run, the 49ers gave up 136 yards on 20 attempts, which calculates to 6.8 yds per run allowed.

If you analyze notching touchdowns, the San Francisco 49ers are sitting at 24.6 points per outing. Collectively, they have an average of 101.4 rushing yds which ranks 25th in the league. The 49ers have recorded 4,865 yds this year. San Francisco has accumulated 192 first downs offensively, and they have committed 73 infractions for 529 yds. They have surrendered the ball 19 times (13 interceptions and 6 lost fumbles). If you're looking at getting the ball into the endzone, San Francisco has attained 25 touchdowns through the air and 12 rushing TD's.

The 49ers are ranking 11th in football when analyzing their defensive abilities, relinquishing 20.9 PPG. They are allowing 4.3 yards per run and 106.1 rushing yards per outing on the campaign. Regarding passing yards, the 49ers have conceded 3,186 yds, which is good for 22nd in the league. They have granted 227.6 total yards per contest through the air, and are relinquishing a completion percentage of 68.8%. Altogether, they are relinquishing 333.6 yds per outing, giving them a rank of 18th in the league. They have relinquished 25 touchdowns through the air, in addition to 9 touchdowns by way of the ground game. On the whole, they have surrendered 1,485 rushing yards through 14 matchups on the year.

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The Colts come into this game with a record of 8-6 on the campaign. The last time they took the field, the Colts walked away with a loss by a score of 18-16 when they faced the Seattle Seahawks. Jonathan Taylor ran the football 25 times for 87 yards, finishing the contest with 3.5 yards per attempt for Indianapolis. Ameer Abdullah was featured in the passing game for the Colts, hauling in 5 balls for 32 yds (6.4 yards per reception). Philip Rivers (1 TD) ended the game with 120 yards on 18-27 through the air while his QB rate was 73.1. He tossed 1 pick and his average yds per pass attempt was 4.4 yds. Indianapolis conceded 22 attempts on the ground for 50 yds (2.3 yards per rush). The Colts pass defense gave up a completion percentage of 61.1%, surrendering 264 yards on 22 out of 36 through the air. The Colts finished the contest with a total of 215 yds while they ran 57 plays (3.8 yds per play). Indianapolis ran for 3.2 yards per carry, finishing the game with 97 yds on 30 attempts.

When it comes to how much they score, the Colts currently rank 6th in the league, by scoring 28.0 points per game. For the season, the Colts sit at 3,206 pass yds and have an average of 229.0 pass yds per contest, which has them ranked 9th in professional football. They maintain an average of 128.5 rush yards per contest, and have carried the football for 1,799 total yards. The Indianapolis Colts average 357.5 total yards per contest, giving them a rank of 8th in professional football. The Indianapolis offense has relinquished 699 yds on 86 violations, which is good for 24th in the NFL if you examine hurting your team. They have tossed 10 picks while yielding 6 lost fumbles, and have been able to record 166 1st downs offensively.

They have given up 18 touchdowns by way of the pass plus 247.6 passing yards per contest, giving them a rank of 31st in professional football. Indianapolis has granted a total of 1,332 running yds (95.1 total yards per contest), plus 13 touchdowns to rushers over the course of this year. The D currently has 18 takeaways (6 forced fumbles and 12 interceptions) on the year. On the whole, they have relinquished 303 total points. The Colts defense has participated in 916 plays, which has them ranked 31st in professional football. The Colts are surrendering 21.6 points per outing, ranking this team at 12th in pro football.

Who will win tonight's 49ers-Colts NFL game against the spread?

Tony's Pick: Take the Colts +6

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