The NFL’s Week 5 spotlight shines on Thursday Night Football, as the San Francisco 49ers (3-1) take on the Los Angeles Rams (3-1) at SoFi Stadium. With playoff implications already in play, the matchup brings high drama, key injuries, and major betting storylines.
According to ESPN, the Rams enter as -8.5-point favorites, while the over/under is set at 43.5. Meanwhile, NFL.com experts unanimously picked Los Angeles, citing San Francisco’s injury crisis. The LA Times highlighted how the Rams’ pass rush and home-field advantage could tilt the balance.
49ers Injury Crisis
The 49ers are entering the game without several star players, including:
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QB Brock Purdy ($53M starter)
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Top three wide receivers
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TE George Kittle (six-time Pro Bowler)
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DE Nick Bosa, former Defensive Player of the Year
Backup QB Mac Jones will start, but his victories this season came against winless or struggling teams, raising doubts about his ability to deliver against the Rams’ top 10 defense.
Rams’ Strong Start and Keys to Victory
The Rams, led by QB Matthew Stafford, have only lost one game this season — and that was due to a late field goal miss. Their defense ranks among the league’s best in pressure rate, giving them a strong edge against an injury-depleted 49ers offense.
If the Rams maintain pressure and avoid turnovers, they could comfortably secure their fourth win of the season. Experts like Dan Parr of NFL.com predict a scoreline around Rams 27-17, while others expect a tighter finish.
Betting Outlook
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Spread: Rams -8.5
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Moneyline: Rams -455, 49ers +350
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Total (O/U): 43.5
ESPN analysts note that betting action is heavily favoring the Rams due to San Francisco’s injuries, but bettors should be wary of division matchups, which often produce closer results than expected.
Expert Picks and Predictions
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NFL.com Consensus: Rams win (all analysts agree)
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Score Predictions: Range from Rams 24-21 to 30-16
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Key Stat: Stafford is 2-5 vs the 49ers since joining LA, but this is his best chance to turn that record around.
How to Watch
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Date: Thursday, October 2, 2025
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Time: 8:15 PM ET
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Where: SoFi Stadium, Inglewood, CA
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Broadcast: Prime Video (streaming exclusive)
The Rams enter as heavy favorites, with their defense expected to overwhelm San Francisco’s backup-led offense. The 49ers will need near-perfect execution to pull off an upset, while Los Angeles looks poised to take control of the NFC West race.