Indianapolis Colts vs. San Francisco 49ers Predictions, Odds, Picks

Oct. 24, 2021
Michael Crosson
VI Betting Expert

The seventh weekend of regular season NFL action will conclude with a prime-time interconference showdown on NBC, as the San Francisco 49ers will host the Indianapolis Colts on Sunday night. Coverage begins at 8:20 p.m. ET.

Score Prediction

Colts 24, 49ers 20

Best Bets

Colts +4

Carson Wentz (IND/QB) Over 1.5 TD Passes (+150)

Indianapolis Colts vs. San Francisco 49ers Predictions

After yielding a disappointing 0-3 record across Carson Wentz’s opening stretch of matchups with Indy, it seemed like an overwhelming majority of bettors quickly hopped off the Colts’ bandwagon – considering Frank Reich’s squad entered Week 4 as slight underdogs against the Dolphins (IND +3).

It’s tough to totally fault Indy for its frustrating offensive issues early on though, considering the Colts clearly spent the first three weeks trying to get comfortable with their new signal-caller – and consecutively matching up against the Seahawks, Rams, and Titans isn’t comforting by any stretch of the imagination.

The Colts have cranked things up a notch across the last three weeks though, considering Indy ended up pounding the Dolphins and Texans in Weeks 4 and 6 (+38) – and dropped a heartbreaker to the red-hot Ravens on Monday Night Football in Week 5 (L, 31-25 OT).

On the other hand, San Francisco has ridden quite the rollercoaster to start the season, considering the Niners opened with a pair of decisive victories over the Eagles and Lions (+14) – but since Week 2, they’ve posted three straight losses against the Packers, Seahawks, and Cardinals.

I’ll take the points with Indy here, as the Colts’ lone defeat since Week 3 came during an overtime thriller against the Ravens – while the Niners have averaged just 19 PPG across their last four contests, and they’ll likely need far more juice than that to take down Indy on Sunday night.

Indianapolis Colts vs. San Francisco 49ers Betting Odds

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The total for Sunday’s matchup is stationed around OU 43 at most shops, which is the lowest bar set for a matchup containing San Francisco so far this year – and the second-lowest set for a matchup containing Indy.

Indianapolis Colts vs. San Francisco 49ers Betting Resources

  • Matchup: AFC South vs. NFC West
  • Date: Sunday, October 24, 2021
  • Venue: Levi's Stadium
  • Location: Santa Clara, California
  • TV-Time: NBC - 8:20 p.m. ET

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Indianapolis Colts Betting Analysis

Straight Up - SU, Against the Spread - ATS, Over-Under (O/U)

  • SU: 2-4
  • ATS: 4-2
  • O/U: 3-3
  • ATS - Home: 2-1
  • ATS - Away: 2-1

After trading for a new starting signal-caller in Wentz during the offseason, the Colts were immediately faced with an enormous challenge to kick things off the new year – as Indy hosted the Seahawks and Rams in Weeks 1 and 2, and then hit the road to face the Titans in Week 3.

The Colts’ 0-3 start wasn’t all that bad, considering they remained competitive for the length of both matchups against the Rams and Titans – and their opening loss to Seattle wasn’t necessarily horrendous either.

Indy has played some excellent football as of late though, considering the Colts are 2-1 across their last three games – and they were extremely close to beating the Ravens in the lone game they lost across that window.

If a few extra bounces ended up going the Colts’ way against L. A. and Baltimore, and Indy was sitting at 4-2 with wins over the Rams and Ravens instead of 2-4 – I’m sure we would be looking at Wentz and company much differently ahead of Week 7 as well.

San Francisco 49ers Betting Analysis

Straight Up - SU, Against the Spread - ATS, Over-Under (O/U)

  • SU: 2-3
  • ATS: 1-4
  • O/U: 2-3
  • ATS - Home: 0-2
  • ATS - Away: 1-2

After falling a field goal shy of beating Green Bay for their third straight victory to open the season (L, 30-28), the Niners drew another tough matchup in the Seahawks in Week 4 – and that’s when things noticeably took a downward turn for San Francisco, as QB Jimmy Garoppolo exited with a calf injury and turned over the keys to the offense to rookie Trey Lance for the remainder of the loss.

Despite their various issues though, San Francisco’s defense still stood tall throughout this brutal stretch, considering the Niners allowed just 21.5 PPG across their last four matchups against the Eagles, Packers, Seahawks, Cardinals – while they currently rank 8th in yardage allowed per play (5.3 YPP). Most people don’t seem overly concerned about the Niners, as they currently own a 2-3 – and have played two-and-a-half games with their backup quarterback.

The Niners played strikingly competitive games against the Eagles and Lions during the opening two weeks of the season though – but if they lost one of those, we would likely be having a much different conversation about how their season panned out so far.

The San Francisco 49ers have failed to cover the spread in eight of their last nine games when playing as favorites. (AP)

Inside the Stats - Indianapolis Colts

  • Record: 2-4
  • Division Standing: 2nd - AFC South
  • Points Scored: 139
  • Points Allowed: 131
  • PS/G: 23.2 (19th)
  • PA/G: 21.8 (11th)

Inside the Stats - San Francisco 49ers

  • Record: 2-3
  • Division Standing: 3rd - NFC West
  • Points Scored: 117
  • Points Allowed: 119
  • PS/G: 23.4 (17th)
  • PA/G: 23.8 (16th)

Key Players to Watch

  • IND: Carson Wentz - QB (124/193, 1,545 yards, 9 TD, INT)
  • IND: Jonathan Taylor - RB (87 carries, 472 yards, 4 TD)
  • SFO: Jimmy Garoppolo - QB (78/118, 925 yards, 5 TD, 2 INT)
  • SFO: Deebo Samuel - WR (31 catches, 548 yards, 3 TD)

Indianapolis Colts vs. San Francisco 49ers Betting Conclusion

After losing an ugly low-scoring battle to Arizona in their previous contest (L, 17-10), the Niners will return from their bye-week as four-point favorites over the visiting Colts – which despite their 2-3 record, marks the fifth matchup San Francisco has been favored in this season.

I’ll take the points with Indy here, as the Colts’ have racked up an average of 27.7 PPG across their latest trio of matchups against the Dolphins, Ravens, and Texans – and Wentz threw a pair of touchdowns passes in each of those affairs, which is why I’m also backing him to throw two more at plus odds on Sunday night.

Indianapolis Colts vs. San Francisco 49ers Betting Trends

  • Indianapolis has won eight straight games when facing a team with a losing record.
  • San Francisco has failed to cover the spread in eight of its last nine games when playing as the favorite.
  • Indianapolis has gone OVER the point total in five of its last six road games.
  • Indianapolis has covered the spread in four of its last six games.

Where to place a bet this NFL Season?

  • Use our exclusive BetMGM Bonus Code VIBONUS1500 to unlock BetMGM’s welcome offer for new sportsbook users!
  • Compare the latest NFL Odds from the best sportsbooks before placing a bet on this week's games.
  • Check out the North Carolina Sportsbooks just before they launch legal online sports betting.