Our NFL experts have readied their 49ers vs. Colts predictions and best bets for Monday Night Football!
From the spread and total to player props and anytime TD predictions, our NFL picks have got you covered for the Week 16 finale from Lucas Oil Stadium.
49ers vs Colts MNF predictions
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49ers vs Colts MNF best bets
49ers -4.5
Josh Inglis believes the San Francisco 49ers are not be respected enough vs. the Indianapolis Colts tonight.
"The 49ers have been discounted all season, posting a 9-5 ATS record, and this is an offense built to win to margin, especially indoors. If Philip Rivers is forced to open things up this week, the mistake potential rises, which only strengthens the case for laying the number."
Over 46.5
Inglis' best bet is the Over, and he lays out the case below.
"This is a spot where context matters more than box scores, and it points clearly toward the Over. The game shifts indoors, Philip Rivers gets another week to settle into this offense, and he’s no longer dealing with the chaos of Lumen Field. On the other side, the San Francisco 49ers are finally healthy on offense and could be one of the strongest units down the stretch."
49ers vs Colts MNF TD picks
Jauan Jennings anytime TD
Ryan Gilbert will ride the hot hand with Jauan Jennings on MNF.
"Christian McCaffrey leads the 49ers with 14 touchdowns this season, but he's -225 to score this week. Instead, I'm looking at wide receiver Jauan Jennings, who has become a key target for the 49ers in recent weeks. Jennings is second on the 49ers with seven touchdowns, and he comes into this Monday Night Football on a three-game scoring streak, including two last week against Tennessee."
49ers vs Colts MNF props
Josh Downs Over 24.5 receiving yards
Jason Logan noted the chemistry between Rivers and Josh Downs last week, and expects that to roll over into Monday Night Football.
"Josh Downs was one of Philip Rivers’ favorite targets in the veteran quarterback’s first start last Sunday. Rivers attempted 27 total passes, and five of those came to Downs, who caught three of those balls for just 13 yards (one for a touchdown). The San Francisco 49ers have a softer secondary than the Seattle Seahawks, and the Niners’ passive zone-heavy schemes are susceptible to slot receivers."
49ers vs Colts odds
49ers vs Colts game info
| Location: | Lucas Oil Stadium, Indianapolis, IN |
| Date: | Monday, December 22, 2025 |
| Kickoff: | 8:15 p.m. ET |
| TV: | ESPN |
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