The San Francisco 49ers (10-4) and the Indianapolis Colts (8-6) meet for Monday Night Football in Week 16 at Lucas Oil Stadium in Indianapolis, Indiana. Kickoff is set for 8:15 p.m. ET (ESPN). Let’s analyze BetMGM Sportsbook’s NFL odds around the 49ers vs. Colts odds and make our expert NFL picks and predictions for the best bets.

The 49ers stayed hot in Week 15, extending their winning streak to 4 with a 37-24 victory over the Tennessee Titans. San Francisco covered as 12.5-point home favorites with the Over (45) cashing. QB Brock Purdy went 23-of-30 for 295 yards and 3 TD, with 2 going to WR Jauan Jennings and 1 to TE George Kittle, who finished with 8 catches for 88 yards.

The Colts’ skid reached 4 games with an 18-16 loss to the Seattle Seahawks. Indianapolis covered as 13-point road underdogs as the Under (41.5) cashed. Making his first appearance in 5 years, 44-year-old QB Philip Rivers threw for 120 yards, 1 TD and 1 INT. RB Jonathan Taylor rushed for 87 yards, while K Blake Grupe went 3-for-3 on field goals.

Indianapolis won the last meeting 30-18 in 2021 and the Colts lead the all-time series 27-19.

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49ers vs. Colts odds

Provided by BetMGM Sportsbook; access USA TODAY Sports Scores and Sports Betting Odds hub for a full list. Lines last updated Sunday at 6:54 p.m. ET.

Moneyline (ML): 49ers -250 (bet $250 to win $100) | Colts +200 (bet $100 to win $200)Against the spread (ATS): 49ers -5.5 (-118) | Colts +5.5 (-102)Over/Under (O/U): 46 (O: -110 | U: -110)

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49ers vs. Colts key injuries

49ers

CB Renardo Green (neck) outDE Yetur Gross-Matos (hamstring) questionableWR Ricky Pearsall (knee/ankle) outLB Jay Higgins (knee) out

Colts

DT DeForest Buckner (neck/rest) questionableCB Sauce Gardner (calf) outWR Anthony Gould (foot) outOT Bernhard Raimann (elbow) outQB Anthony Richardson (eye) outS Daniel Scott (knee) out49ers vs. Colts picks and predictionsPrediction

49ers 21, Colts 10

PASS.

These are 2 teams going in opposite directions. It’s hard not to be all in on San Francisco against a 44-year-old quarterback playing only his second game in the last 5 years. I’ll take my wager to the spread.

BET 49ERS -5.5 (-118).

Everything about this matchup lines up for the 49ers, while Indianapolis feels like a team just trying to get through the season. The Colts have dropped 4 straight and have scored 20 points or fewer in 5 of their last 6 games. That’s not the profile of an offense I’m eager to back, especially against a defense as physical and disciplined as San Francisco’s.

The 49ers, meanwhile, are rolling. They’ve covered in 4 straight wins and look increasingly comfortable on offense with Purdy running the show. Even with injuries across the roster, San Francisco still ranks near the top of the league on third down and through the air, which matters against an Indianapolis defense that struggles to get off the field. This game being indoors also removes any weather variables that might slow the Niners down.

I also don’t trust the Colts’ quarterback situation at all. Rivers showed plenty of rust last week, and asking him to keep pace with a hot San Francisco offense feels like a stretch. Indianapolis may hang around early, but I expect the 49ers to pull away as the game settles in. Anything under a touchdown is playable.

BET UNDER 46 (-110).

Indianapolis’ offense just isn’t built to push the pace right now, especially with Rivers back under center. Last week showed they want to shorten games and lean on Taylor, not trade scores. San Francisco’s defense has been solid during this win streak, and the Colts have stayed Under in 4 of their last 6. This feels like a grind-it-out game where 20 points might be enough to win.

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