Best NFL Picks and Predictions Today (How to Bet 49ers vs. Colts on Monday Night Football in NFL Week 16)

Breaking down the best picks and predictions for the San Francisco 49ers-Indianapolis Colts matchup on Monday night.

San Francisco 49ers tight end George Kittle is a great prop target on Monday. / Cary Edmondson-Imagn Images

Philip Rivers and the Indianapolis Colts are attempting to stay alive in the AFC playoff race on Monday night when they host the San Francisco 49ers.

Brock Purdy and the 49ers just need a win to clinch a playoff spot in the NFC, and they are on a four-game winning streak since the starting quarterback returned from a toe injury. Purdy has led the 49ers to a 5-1 mark this season, and they’re still in play for the NFC West crown with a few games left in the regular season.

Oddsmakers have set the 49ers as favorites in this game, but the spread has moved quite a bit since opening with San Francisco as a 4.5-point favorite. 

While Rivers was able to lead the Colts to a cover – and nearly an upset win – in his first start since 2020, the betting market clearly isn’t sold on the 44-year-old saving Indy’s season.

The Colts have dropped four in a row to fall out of a playoff spot in the AFC, but they have two divisional games to close out the regular season where they could make up ground. 

As for this game, the SI Betting team has been making a ton of picks in the lead up to Monday night, and I’ve put together some of our favorites in a one-stop shop for bettors tonight.

Here’s a breakdown of each pick and the latest odds for this Week 16 clash. 

Best NFL Picks and Predictions for 49ers vs. Colts

Odds via DraftKings Sportsbook.

• Indianapolis Colts Moneyline (+235) vs. San Francisco 49ers – Iain MacMillan
• Jonathan Taylor OVER 98.5 Rushing Yards (-115) – Peter Dewey
• George Kittle OVER 59.5 Receiving Yards (-118) – Peter Dewey
• Christian McCaffrey Anytime TD (-240) – Peter Dewey

Indianapolis Colts Moneyline (+235) vs. San Francisco 49ers – Iain MacMillan

Ahead of Week 16, SI’s NFL betting insider Iain MacMillan shared his favorite bet for this game in his Road to 272 column, and he’s taking the Colts to pull off the upset: 

Philip Rivers is back in action, and while he may not have looked like his old gunslinger self, he's still extremely smart and will make very few mistakes. People are also quick to forget that he had to face one of the best defenses in the NFL in his first game since 2021. Now, he has a much easier matchup ahead of them against the injured 49ers defense that ranks in the bottom 10 of the NFL, especially when it comes to stopping the run.

Daniel Jones' injury didn't break this Colts team. The Colts still rank fourth in overall DVOA and sixth in Net Yards per Play. It could also be time to sell high on this 49ers team. Don't be surprised if Indianapolis pulls off this upset and keeps its playoff hopes alive.

Jonathan Taylor OVER 98.5 Rushing Yards (-115) – Peter Dewey

Jonathan Taylor nearly reached 90 rushing yards against the No. 1 run defense (in EPA/Rush) in the NFL last week, making him an intriguing bet in Week 16: 

Taylor enters Week 16 at No. 2 in the odds to win Offensive Player of the Year, and he’s in a good spot to have a big game on the ground against this San Francisco defense.

The 49ers rank 21st in the NFL in EPA/Rush, which is a far cry from the Seattle Seahawks (No. 1 in EPA/Rush), who Taylor faced last week. In that game, Taylor picked up 87 yards on 25 carries, showing that he’s going to handle a major workload with Rivers under center.

Taylor has 99 or more rushing yards in just five games this season, but he’s handled 21 or more carries in each of his last three games. 

That increased workload should go a long way for the Colts star, especially since San Francisco is allowing 4.3 yards per carry this season. 

George Kittle OVER 59.5 Receiving Yards (-118) – Peter Dewey

The Colts have struggled to defend the tight end position, which sets up well for George Kittle in Week 16: 

This is a great matchup for George Kittle, who has five straight games with 67 or more receiving yards.

The Colts have given up the fifth-most receiving yards to tight ends (928) this season and the sixth-most receptions (86).

Kittle has easily cleared this line in each of Purdy’s last four starts, and he should be the focal part of the 49ers passing game on Monday. Since Purdy returned, Kittle has been targeted 30 times in four games.

He should torch this Indy secondary that has dealt with a bunch of injuries in 2025. 

Christian McCaffrey Anytime TD (-240) – Peter Dewey

This is a little bit of an obvious prop, but CMC has found the end zone in five games in a row with Purdy at quarterback: 

I know, laying this price for McCaffrey is not ideal, but the 49ers running back is nearly a lock to score in every game this season.

He’s found the end zone in 10 of his 14 matchups, and the star back has scored in every game since Purdy returned to the lineup.

In fact, CMC has six scores over that four-game stretch and 14 total touchdowns in the 2025 campaign (nine rushing, five receiving). Arguably the best dual-threat back in the NFL, McCaffrey is worth a look against a Colts team that has been very beatable through the air (allowing the second-most passing yards in the league) despite holding teams to just 3.7 yards per carry on the ground.

McCaffrey is as matchup-proof as a player gets when it comes to this market.

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Odds refresh periodically and are subject to change.

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