49ers vs. Rams Score Prediction for NFL Week 1 (Who Wins Crucial NFC West Showdown?)

A massive NFC West battle kicks off this year’s Thursday Night Football action, as Matthew Stafford and the Los Angeles Rams take on the San Francisco 49ers in the first-ever NFL game in Australia.

These teams have employed different travel plans ahead of this Week 1 matchup, with the Rams deciding to arrive much closer to game time to help deal with the crazy travel being put on them to start the season.

Stafford and the Rams are the favorite to win the Super Bowl this season, and they have a loaded roster of star veterans, including Myles Garrett, Trent McDuffie, Puka Nacua, Davante Adams, Kyren Williams and Aaron Donald (out on Thursday), who came out of retirement to play this season.

That’s going to make things tough on a San Francisco team that dealt with a ton of injuries last season, but is relatively healthy entering Week 1. Kyle Shanahan’s club battled some huge losses to make the playoffs and win a postseason game in 2025.

So, who has the edge in this Week 1 showdown?

All season long, the SI Betting team will be using the latest odds, insight from oddsmakers and analysis to predict the final score in nearly every regular season game.

The Rams are 3.5-point favorites in a neutral site game in Week 1, and SI Betting’s NFL betting insider Iain MacMillan thinks we could see a close game on Thursday night.

49ers vs. Rams Odds, Spread and Total

Odds via BetMGM

Spread

49ers +3.5 (-108)
Rams -3.5 (-110)

Moneyline

49ers: +165
Rams: -200

Total

48.5 (Over -108/Under -110)

There has been some line movement in this game, something that I noted in SI Betting’s Sportsbook Insiders earlier this week:

“Not a lot of significant line movement at this time, most would be driven by injury news to quarterbacks. But the Rams did move from -2.5 to -3.5 vs. the 49ers,” Christian Cipollini, Senior Trading Manager, BetMGM told Sports Illustrated. “Combo of the 49ers dealing with injuries to WR/TE and the Rams trading for Myles Garrett and adding Donald.”

These teams have both covered five times in their last 10 games against each other, but this is an interesting neutral site matchup. The Rams would have been favored by at least one more point had this game been played in L.A., according to Cipollini.

49ers vs. Rams Score Prediction

Earlier this week, SI Betting’s senior editor Iain MacMillan shared his favorite bet for this game in his Road to 272 column – where he bets on every NFL game throughout the season:

After the offseason they had, there is more hype behind the Los Angeles Rams this season than I think I've ever seen for a team ahead of the opening kickoff. Maybe they'll end up being as good as advertised, but I think this is a perfect spot to sell high on hype. Until they prove they're as good as the betting market is treating them, I'm going to hang back when it comes to betting on them.

Not only that, but I'm high on the 49ers this season. They had some of the worst injury luck in football last year, but still managed to finish 10th in DVOA. Now, they're relatively healthy, and I expect them to overachieve relative to how the betting market is evaluating them.

Not only that, but this game is in Australia, and the Rams plan to do a "drive-by,” showing up and immediately playing instead of arriving a few days ahead of time to acclimatize. I don't know if that's the smartest strategy for them to utilize.

I'll jump on the 49ers getting more than a field goal in this divisional matchup.

This should be a close game, especially since there are a lot of travel concerns on both sides. Which decision will be the correct one?

This also may be the healthiest the 49ers are at certain positions, considering all of the injury issues they’ve had in recent seasons. It’s hard to look past the fact that San Fran won double-digit games with Fred Warner and Nick Bosa missing the majority of the season in 2025 and Brock Purdy missed eight games with a toe injury.

One trend to watch: Shanahan has an 11-7 record against Sean McVay in their respective careers, and the 49ers are 22-17 as road underdogs since Shanahan became their head coach in 2017.

The Rams have a ton of talent, and I like the Rams to win this game, but I agree with MacMillan that it could end up with San Francisco within a field goal.

Final Score Prediction: Rams 27, 49ers 24

Odds refresh periodically and are subject to change.

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