49ers vs. Colts Final Score Prediction for NFL Week 16 (Can 49ers Cover on Road?)

The 49ers are road favorites on Monday night.

The San Francisco 49ers and quarterback Brock Purdy are favored on Monday. / Cary Edmondson-Imagn Images

Monday Night Football in Week 16 features a battle between two playoff hopefuls in the San Francisco 49ers and Indianapolis Colts.

All San Francisco has to do to clinch a playoff spot is win, and the 49ers are favored by nearly a touchdown in this primetime matchup, despite being on the road.

The Colts, on the other hand, have dropped four games in a row and are playing 44-year-old Philip Rivers at quarterback. Rivers led the Colts to a cover – and nearly a win – in Week 15, but can he compete with this vaunted San Fran offense? 

Brock Purdy has led the 49ers to four wins in a row since he returned from a turf toe injury, and San Francisco is still in play to win the NFC West.  

All season long, the SI Betting team has been sharing final score predictions for games in the NFL, and this week is no different! These predictions are a fun way for us to predict the score while also giving bettors our thoughts on the spread and total.

So, here’s a look at how I’m betting on this Monday Night Football battle between two teams headed in different directions. 

49ers vs. Colts Odds, Spread and Total

Odds via DraftKings Sportsbook.

Spread

• 49ers -6 (-115)
• Colts +6 (-105)

Moneyline

• 49ers: -290
• Colts: +235

Total

• 46.5 (Over -102/Under -118)

The Colts are set to start Rivers for the second game in a row, and oddsmakers have shifted this line quite a bit since it opened on Sunday night after Week 15. Indy opened as a 4.5-point underdog, but that line has since moved to Colts +6, as they’ve dropped four games in a row to fall to 8-6 this season. 

There are some interesting trends to follow in this matchup, especially after the Colts easily covered as double-digit underdogs in Week 15. Indy is 3-1-1 against the spread as a dog this season while the 49ers are 6-2-1 against the spread when favored.

San Francisco is also 5-1 when Brock Purdy starts in 2025. 

49ers vs. Colts Final Score Prediction

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.

While MacMillan is betting on an upset in this matchup, I think the 49ers are one of the most underrated teams in the league.

San Francisco has won four games in a row since Brock Purdy returned to action, and it’s 6-2-1 against the spread when favored. The 49ers’ offense is elite, and I think it will be able to score enough to beat a Colts team that is simply a shell of what it was earlier in the campaign. 

Maybe Indy covers with this line moving from 4.5 to 6, but the 49ers should win.

Final Score Prediction: 49ers 24, Colts 19

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Odds refresh periodically and are subject to change.

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