San Francisco 49ers vs Los Angeles Rams Prediction, Odds and TNF Picks for Today, 10/02/25

The 49ers and Rams are at the top of the NFC West, 2 perennial elites that once again appear on a collision course. Despite their 3-1 records, they don’t feel like similar programs right now. San Francisco is coming off a bad loss where they turned it over 4 times against the upstart Jaguars, who were a 3.5-point underdog. Furthermore, the 49ers’ rushing attack continues to be pedestrian, gaining just 88 rush yards per game (28th). Mac Jones will be in command for the 49ers after Brock Purdy was ruled out, and will lead a talented group that’s top-5 in total offense, although they have been slow to capitalize and score points (20 ppg, ranked 22nd). Their defense is likely playing over its head at this point, with injuries mounting and offenses starting to figure out their holes. The 2025 49ers are starting to run into the same problems that affected their 2024 campaign, which is a cause for concern.

Historically, Kyle Shanahan and the 49ers have done well in this series (11-6 against McVay), but the Rams are a different animal this season. Indianapolis gave away some points in their Week 4 battle, but the home team also took advantage of Indy’s mistakes. Additionally, Matthew Stafford’s connection with Puka Nacua proved elite once again (13 catches for 170 yards and a touchdown). It was an impressive response after blowing a sure win in Philadelphia last Sunday, arguably a champion’s response. On both sides, the Rams seemingly have the talent and firepower to keep up with any team in the NFL, and by playing mistake-free football, they proved too much for their previously undefeated visitors last Sunday. 

While Shanahan has typically found success against the Rams, this checks out as a nice opportunity for the 49ers’ regression. The question is, how good are the Rams? And how different is the matchup at this juncture? Based on our power ratings, the Rams are clearly the better team, and they should be able to secure a statement win on TNF to take control of the NFC West.

49ers vs Rams prediction: Rams -5.5 (-110) available at time of publishing. Playable to 6.

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