49ers vs. Colts Prediction & Opening Odds for Monday Night Football: NFL Week 16 Picks

With Philip Rivers set to start another game for Indianapolis this week, my 49ers vs. Colts prediction backs San San Francisco to win easily on the road at Lucas Oil Stadium.

The 49ers are a 5.5-point betting favorite over the Colts on Monday Night Football in Week 16. Kickoff from Indianapolis is slated for 8:15 p.m. ET (ESPN/ABC). Let's dive into our NFL Week 16 predictions.

🏈 Early 49ers vs. Colts prediction & betting preview

Stay ahead with the rest of our early NFL picks for Week 16.

49ers -5.5 (-105) ⭐⭐⭐⭐⭐

This line's too low, suggesting the 49ers would only be 3-point favorites if this were in Santa Clara. They've covered in four straight, winning by 15.3 points per game. 

While the Colts covered on Sunday, Sam Darnold threw no touchdowns and finished with a QBR of just 44. Although Philip Rivers was decent, the Colts’ cover was due to the Seahawks scoring fewer than 19 for the first time since Week 1.

These -105 odds at DraftKings for the 49ers to win by six-plus are the best available. They carry an implied probability of 51.22%. A $10 ticket profits $9.52.

📊 Live 49ers vs. Colts odds: Monday Night Football

See the latest NFL odds for every game in Week 16.

49ers vs. Colts opening odds

• Moneyline: 49ers -255 | Colts +211
• Spread: 49ers -5.5 (-110) | Colts +5.5 (-110)
• Over/Under: Over 46 (-110) | Under 46 (-110)

49ers vs. Colts line movement

The 49ers were 7-point betting favorites on the lookahead line at DraftKings on Sunday morning. The line then dropped to 4.5 after the Colts covered against the Seahawks and has since been bet back up to 5.5.

While the market is being reactive right now - since Rivers’ value was unknown heading into Week 15 - efficient markets like NFL sides tend not to overreact by the closing line. I expect this spread to close closer to 6.5 as limits rise throughout the week, so bet the 49ers now if you like them, and wait until post if you want to bet the Colts.

📈 49ers vs. Colts trends & betting notes: MNF

• 49ers are 4-0 ATS in their last four games
• 49ers are 5-0 ATS as road favorites this season
• Colts are 2-3-1 ATS in their last six games
• Colts are 3-0 ATS vs. 49ers in last three head-to-head meetings (dating back to 2013)

📺 How to watch 49ers vs. Colts: Monday Night Football

• Date: Monday, Dec. 22
• Kickoff: 8:15 p.m. ET
• Location: Lucas Oil Stadium (Indianapolis)
• TV: ESPN/ABC