The Week 5 edition of Thursday Night Football features a couple of 3-1 teams, with the Los Angeles Rams favored by 7 over their NFC West rival, the San Francisco 49ers.
While the Rams look poised for a deep playoff run, the 49ers are simply trying to hold things together after being ravaged by injuries during the first month of the season.
My 49ers vs. Rams predictions believe this is San Francisco’s biggest test to date. Along with the adversity of traveling on a short week without key players, my NFL picks think the Niners will have trouble staying competitive on October 2.
49ers vs Rams prediction
49ers vs Rams Best bet: Rams -7 (-105)
Coming into the season, much was made of the San Francisco 49ers' easy schedule. They’ve been able to take full advantage so far, but they’ve hardly been impressive.
We saw them squeak by the Seahawks, Saints, and Cardinals in their opening three games, then lose as a home favorite against the Jaguars in a game where they were down by 12 points with less than five minutes left on the clock.
Now the level of competition will rise significantly against a Los Angeles Rams team that typically doesn’t play down to the competition. Los Angeles is on a run that’s seen them go 11-4 ATS in their last 15 games as a favorite, with just one outright loss in this span.
I think this game sets up very nicely for Matthew Stafford and a Rams pass attack that ranks fifth in yards per pass attempt.
Stafford should have a lot of time to work as the 49ers are struggling to disrupt opposing QBs. They come in ranked 29th in pressure rate and have just five sacks.
San Francisco also comes in at 25th in opponent completion percentage, and they’ve yet to face a passing game of the caliber of the Rams.
While the 49ers’ defense will likely have its hands full, I think the offense will have trouble keeping up.
Brock Purdy hasn’t been good this season with four interceptions thrown in two games. He could be down another weapon as well with leading receiver Ricky Pearsall questionable to play due to a knee injury.
While Christian McCaffrey has looked good this season, this 49ers offense isn’t even remotely close to where they were in 2023 when this era of the team was at its peak. That’ll happen when you remove George Kittle and prime versions of Deebo Samuel and Brandon Aiyuk from a lineup.
As a result of the watered down offense, Purdy simply doesn’t have enough to work with and could start to get exposed even more. As a whole, let’s not forget an injury-ravaged 49ers team went 1-7 to close out 2024, and it looks like history could repeat itself in 2025.
49ers vs Rams TNF same-game parlay
The path to winning and covering will come through the air for the Rams.
Stafford should have plenty of time to work against this light pass rush of the 49ers, who've yet to play a top-tier offense this season. Stafford will have the ability to pick apart a defense that ranks 25th in opponent completion percentage.
Expect Davante Adams, who's had 50+ yards in every game this season while ranking tied for the league lead in red-zone targets, to benefit.
49ers vs Rams 4-leg SGP
- Rams moneyline (-310)
- Matthew Stafford Over 235.5 passing yards (-112)
- Davante Adams Over 54.5 receiving yards (-114)
- Davante Adams anytime TD (+115)
Our big-ticket SGP: Problems for Purdy
It's been a shaky start to the season for Purdy, who's thrown four picks in two games. I expect the 49ers to be playing from behind, which will force him to throw more.
49ers vs Rams 5-leg SGP
- Rams moneyline (-310)
- Matthew Stafford Over 235.5 passing yards (-112)
- Davante Adams Over 54.5 receiving yards (-114)
- Davante Adams anytime TD (+115)
- Brock Purdy Over 0.5 interceptions (-125)
49ers vs Rams odds
- Spread: San Francisco +7 | Los Angeles -7
- Moneyline: San Francisco +270 | Los Angeles -340
- Over/Under: Over 46.5 | Under 46.5
49ers vs Rams betting trend to know
The Rams have covered the 2Q Spread in 15 of their last 19 games (+10.60 Units / 48% ROI). Find more NFL betting trends for 49ers vs. Rams.
How to watch 49ers vs Rams
| Location | SoFi Stadium, Inglewood, CA |
| Date | Thursday, October 2, 2025 |
| Kickoff | 8:15 p.m. ET |
| TV | Amazon Prime |
49ers vs Rams latest injuries
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