Week 5 of Thursday Night Football pits two 3-1 teams against each other, with the Los Angeles Rams favored by 8.5 points over the San Francisco 49ers.
While the Rams appear poised for a deep playoff run, the 49ers are simply trying to stay afloat after a brutal first month plagued by injuries.
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 break down why the Niners will have trouble staying competitive on October 2.
Kickoff is set for 8:15 p.m. ET from SoFi Stadium in Inglewood, with the game airing on Prime Video.
49ers vs Rams prediction
49ers vs Rams Best bet: Rams -8.5 (-110)
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.
To make matters even more challenging for the 49ers, Mac Jones will step in for Brock Purdy, and he'll be working with a skeleton crew of wide receivers, with both Ricky Pearsall and Jauan Jennings set to miss the game.
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.
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
- Matthew Stafford Over 234.5 passing yards
- Davante Adams Over 53.5 receiving yards
- Davante Adams anytime touchdown
Our big-ticket SGP: Jones adds to Niners' woes
I expect the 49ers to be playing from behind, which will force Jones to throw more and potentially make a mistake.
49ers vs Rams 5-leg SGP
- Rams moneyline
- Matthew Stafford Over 234.5 passing yards
- Davante Adams Over 53.5 receiving yards
- Davante Adams anytime touchdown
- Mac Jones Over 0.5 interceptions
49ers vs Rams game predictions
49ers vs Rams moneyline prediction
The Rams don't play down to the competition, as they have wins in 14 of their last 15 games as a favorite.
I expect them to take full advantage of this watered-down version of the 49ers.
49ers vs Rams spread prediction
San Francisco tends to get by on reputation based on success from previous seasons and having respectable coaching, but this beat-up version of the team is probably a Bottom-10 team in the NFL.
Don't be surprised if L.A. lays the smack down on their division rival and wins by 10+ points.
49ers vs Rams Over/Under prediction
49ers vs Rams odds
- Spread: San Francisco +8.5 (-110) | Los Angeles -8.5 (-110)
- Moneyline: San Francisco +350 | Los Angeles -450
- Over/Under: Over 44.5 (-110) | Under 44.5 (-110)
49ers vs Rams betting trend to know
Los Angeles has covered the 2Q Spread in 15 of its 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 |
Learn how to live stream 49ers vs. Rams for free.
More Thursday Night Football picks and odds from Covers
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- 49ers vs. Rams computer picks
- Matthew Stafford prop picks
- Thursday Night Football odds
49ers vs Rams latest injuries
Brock Purdy has been ruled out for tonight’s game against the Rams due to turf toe.
The 49ers announced that Mac Jones will start in Purdy’s place, with multiple media outlets reporting the decision on Thursday morning. There's no doubt the Niners will miss Purdy's elite processing speed in Shanahan’s full-field, motion-heavy play-action game.
So, how will things look tonight with Jones? Bettors should expect a tighter, more risk-averse script with heavier early down runs and screens through Christian McCaffrey, more quick-game from shotgun, mirrored half-field reads, and fewer deep-over/play-action shot sequences.
Protection will be prioritized with more six- and seven-man looks and defined launch points to keep Jones clean. The net effect is lower explosive-play volatility but steadier drive sustainability. Defenses may squeeze the box and squat on underneath windows unless Jones proves he can hit outside the numbers.
49ers vs Rams weather
Expect classic SoCal football weather in Inglewood tonight: dry and mild, with temperatures easing from the low 70s around kickoff into the mid-to-upper 60s by the second half. Skies trend mostly clear to partly cloudy, and rain isn’t in the picture.
In short, pleasant conditions outside (and even more so under SoFi’s translucent roof).
On-field impact should be subtle. With no meaningful precipitation and typically light evening breezes, quarterbacks can spin it and kickers should get near-“indoor” reliability; the ball should carry normally, and footing on the fast turf will favor sharp cuts and timing routes.
If a shallow marine layer sneaks in late, it could add a touch of moisture to the ball and make returns/ball security marginally trickier, but overall, the weather gives neither the 49ers nor Rams a distinct edge.
Monitor gametime conditions with our live NFL weather info and learn how weather impacts NFL betting.
Odds are correct at the time of publishing and are subject to change.
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