The San Francisco 49ers host the Los Angeles Rams this Sunday in one of the most important games of the season for both teams, as the 49ers already hold wins over all three divisional rivals and sit at 3-0 in the NFC West.
For the Rams, who have lost only two games this year — one of them to the 49ers — the next two weeks will be crucial for their hopes of earning the NFC’s No. 1 seed, with a matchup against the Seattle Seahawks following this Week 10 clash with San Francisco. Here’s how we preview the second meeting between these teams this season.
What Are The Main Matchups Between the 49ers and Rams in Week 10?
The NFC West is the most competitive division in the 2025 NFL season. Right now, three teams remain legitimate contenders for the title, with the Rams emerging as favorites but the 49ers and Seahawks close behind. The first matchup between the 49ers and Rams this year showed just how tight this race will be.
In their Week 5 game, the 49ers traveled to SoFi Stadium despite multiple injuries and pulled off a 26-23 overtime win, thanks to an almost flawless game plan from Kyle Shanahan. San Francisco built an early lead, went into halftime up by two possessions, and held off the Rams in overtime.
This time, however, the 49ers will be without their most disruptive defensive player, who was crucial in stopping Kyren Williams on a key fourth down that sealed the previous victory. With Fred Warner sidelined, San Francisco’s defense faces a major challenge against the NFL’s sixth-ranked offense in the PFSN Offense Impact metric.
One of the key matchups will feature Matthew Stafford attacking the 49ers’ secondary. San Francisco’s pass rush has generated just 11 sacks this season, and the secondary has recorded only one interception. Without the ability to pressure the quarterback or create turnovers, Stafford should have a big day throwing to Puka Nacua and Davante Adams.
Another important battle will be between the Rams’ defensive front and the 49ers’ offensive line. Los Angeles ranks third in the league with 27 sacks and sits second overall in the PFSN Defense Impact metric.
Shanahan will once again need to craft an efficient game plan that works the middle of the field with short passes, as he did in Week 5. The return of George Kittle is encouraging, and Christian McCaffrey could find success running outside against Jared Verse, who has 12 missed tackles against the run — the worst mark in the NFL.
49ers vs. Rams Prediction
Right now, the Rams are clear Super Bowl contenders and widely viewed as the league’s best team, while the 49ers continue to deal with injuries that have thinned their roster week by week. Even so, this matchup always delivers competitive games and features two of the most respected coaches in modern football: Shanahan and Sean McVay.
This game will likely be decided in the final minutes. While the Rams hold the advantage on paper, Shanahan has a history of designing strong game plans against McVay that offset roster issues and turn these contests into high-level tactical battles. Heading into Week 10, Shanahan holds an 11-7 head-to-head advantage over McVay.
In 2024, the Rams swept the 49ers with two one-possession wins. In 2025, we predict that the 49ers will take both matchups.
Prediction: 49ers 24, Rams 23
