Colts vs. 49ers prediction, odds, start time: ‘Monday Night Football’ picks, best bets from proven model

Teams streaking in opposite directions will meet on ‘Monday Night Football’ as the San Francisco 49ers visit the Indianapolis Colts. The Niners (10-4) have won four straight, all of them coming by multiple scores, including a 37-24 win over Tennessee in Week 15. The Colts (8-6), meanwhile, are riding a four-game losing streak and fell to Seattle, 18-16, last week. Quarterback Philip Rivers, who came out of retirement last week following Daniel Jones’ Achilles injury, will start again for the Colts with rookie Riley Leonard backing him up. Cornerback Sauce Gardner (calf) is out for Indianapolis. Ricky Pearsall (knee, ankle) is out for the Niners. 

Kickoff is at 8:15 p.m. ET from Lucas Oil Stadium in Indianapolis. The latest 49ers vs. Colts odds from DraftKings Sportsbook have San Francisco as the 4.5-point road favorite, while the over/under for total points scored is 46. Before making any Colts vs. 49ers picks, be sure to see the NFL predictions from SportsLine’s projection model.

The model, which simulates every NFL game 10,000 times, is up well over $7,000 for $100 players on top-rated NFL picks since its inception. The model enters Week 16 on a 52-37 run on top-rated picks dating back to 2024. Anybody following its NFL betting picks at sportsbooks and on betting sites could have seen strong returns.  

Now, the model has zeroed in on San Francisco vs. Indianapolis. You can head to SportsLine now to see its picks. Here are several NFL odds and betting lines for Colts vs. 49ers:

Football Why the 49ers can cover

The Niners have covered in each contest of their four-game win streak, while Brock Purdy is 5-1 ATS this season. San Fran also has a huge primetime advantage when it comes to the spread, as it has covered in all three such games this year, while Indy is 0-5 ATS over its last five under the bright lights of primetime. Despite batting major injuries all year, the Niners still rank among the top four in both third-down offense and passing offense. The Colts’ offense should have difficulty keeping up with the 49ers as Indianapolis has scored 20 or fewer points in four straight games. See which team to back at SportsLine.

Football Why the Colts can cover

The Colts have owned this series recently, winning five straight overall matchups and going 9-3 over the last dozen home meetings. Indy controls the trenches, leading the NFL in rushing touchdowns while ranking second by allowing just 3.7 yards per rush. The ground game is already a struggle for the 49ers, who rank 31st with 3.5 yards per carry, and Rivers should find more success in his second week back. He’s had a full week in the practice facility, is at home instead of a hostile environment like Seattle, and the Niners rank dead last in the NFL in defensive sacks. See which team to back at SportsLine. 

How to make Colts vs. 49ers picks

For 49ers vs. Colts on ‘Monday Night Football,’ the model is leaning Over the total, projecting 52 combined points. It also says one side of the spread hits well over 50% of the time. See what it is at SportsLine.

Who wins Colts vs. 49ers, and which side of the spread hits in well over 50% of simulations? Visit SportsLine now to see which side of the 49ers vs. Colts spread you need to jump, all from the model that is 52-37 on top-rated picks since 2024, and find out.