Colts vs. 49ers prediction, odds: ‘Monday Night Football’ picks from 10,000 simulations

Teams flying in opposite directions will meet on Monday Night Football. San Francisco 49ers visit Indianapolis Colts. The Niners (10-4) have won four straight, all by varying points, including a 37-24 win over Tennessee in Week 15. The Colts (8-6), meanwhile, are on a four-game losing streak and lost to Seattle 18-16 last week. Quarterback Philip Rivers, who came out of retirement last week due to Daniel Jones' Achilles injury, will start again for the Colts, supported by rookie Riley Leonard. Cornerback Sauce Gardner (calf) is out of Indianapolis. Ricky Pearsall (knee, ankle) is out for the Niners.

Kickoff will take place at 8:15 pm ET at Lucas Oil Stadium in Indianapolis. The latest 49ers vs. Colts odds from DraftKings Sportsbook show San Francisco as a 4.5-point road favorite with the over/under on total points scored at 46. Before making any Colts vs. 49ers picks, be sure to see NFL projections based on SportsLine's projection model.

The model, which simulates every NFL game 10,000 times, costs more than $7,000 for $100 top players. NFL Pick since its creation. The model enters Week 16 with a 52-37 record in the top-rated samples going back to 2024. NFL Betting poking around in bookmakers and further betting sites could see strong profits.

The model is now focused on San Francisco vs Indianapolis. You can head over to SportsLine now to see his picks. Here are a few NFL odds and betting lines for Colts vs. 49ers:

Why the 49ers might be covering.

The Niners played every game of their four-game winning streak while Brock Purdy is 5-1 ATS this season. San Francisco also has a huge primetime advantage when it comes to the spread, having appeared in all three of those games this year, while Indy is 0-5 in points over its last five games under the bright lights of primetime. Despite dealing with significant injuries throughout the year, the Niners still rank in the top four in both third-down offense and passing offense. The Colts offense will have a hard time keeping up with the 49ers as Indianapolis has scored 20 points or fewer in four straight games. Find out which team to support at SportsLine.

Why the Colts might cover

The Colts have owned the series recently, winning five straight overall and going 9-3 in their last dozen home games. Indy controls the trenches, leading the NFL in rushing touchdowns and ranking second, 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 do better in Week 2 back. He's spent a full week in practice, he's at home rather than in a hostile environment like Seattle, and the Niners rank last in the NFL in defensive sacks. Find out which team to support at SportsLine.

How to choose between the Colts and 49ers

For the 49ers against the Colts on “Monday Night Football,” the model is ahead of the total, projecting 52 points. It also states that one side of the spread reaches more than 50% of the time. See what it's all about at SportsLine.

Who will win Colts vs. 49ers and which side of the spread ends up in over 50% of simulations? Visit SportsLine now to find out which side of the 49ers vs. Colts you need to jump, all from a 52-37 model on the highest rated picks from 2024.and find out.