NFL Thursday Night Football: Los Angeles Rams vs San Francisco 49ers preview, betting tips & prediction

The Rams lead the way as 3.5-point favourites on the NFL Week 1 odds, while the 49ers lag as 8/5 underdogs on the money line, with the points total pegged at 48.5.

Last season, the Rams went 12-5 against the spread during the regular season and reached the NFC Championship Game for the first time since their victory in Super Bowl 56 almost five years ago. San Francisco covered 11 of 17 regular-season games in 2025 and returned to the NFL playoffs after a one-year absence, but were bounced by Seattle in a crushing 41-6 defeat in the NFC Divisional Round.

These NFC West rivals split last year’s two meetings. The Niners claimed 26-23 in overtime as an 8.5-point underdog in their visit to Los Angeles in Week, but the Rams answered with a 42-26 road victory a month later.

Four of the past five head-to-head meetings between these squads have been won by the Rams, but LA is only 8-11 overall against San Francisco during the Sean McVay/Kyle Shanahan era.

Kickoff on this NFL Week 1 betting matchup at the Melbourne Cricket Ground is scheduled for 1.35am BST on Friday, September 11, or 10:35 a.m. local time in Melbourne. The game will be streamed live on Netflix.

Neither team has a true home-field advantage, although Los Angeles is officially designated the home team. San Francisco arrived in Australia nearly a week before kickoff to acclimate, while the Rams opted for a much later arrival.

Nick Bosa is expected to play after recovering from the ACL injury that ended his 2025 season, but San Francisco suffered a major blow this week when starting defensive tackle Alfred Collins tore his patellar tendon during practice in Melbourne, putting an end to his season before it begins. Defensive end Sam Okuayinonu is also sidelined with a broken foot.

George Kittle has been limited while returning from a torn Achilles but is trending toward playing. Brock Purdy should otherwise have his main weapons available, including McCaffrey and offseason addition Mike Evans.

Christian McCaffrey’s rushing market stands out, with last season’s NFL Comeback Player of the Year offering good value on the NFL player props at 7/10 to score a touchdown anytime. Indeed, San Francisco’s clearest path to slowing Matthew Stafford is controlling possession, and McCaffrey should see a heavy workload.

Aaron Donald will not play after recently ending his two-year retirement. McVay confirmed Donald will remain in Los Angeles rather than travel to Australia. The Rams still have reigning Defensive Player of the Year Myles Garrett, who recorded an NFL-record 23 sacks last season. Garrett has dealt with knee swelling, but McVay says he’ll be ready.

Stafford is coming off an MVP season after throwing for 4,707 yards and an NFL-high 46 touchdowns. Puka Nacua remains his top target after leading the NFL with 129 receptions last year.

Kyren Williams is also worth considering in the Anytime TD odds as a short 3/4 bet.  Williams remains the Rams’ lead back and should get the short-yardage opportunities in a matchup where San Francisco has suddenly become thin along the defensive line, and should not be overlooked to record 2+ TDs.

San Francisco’s early arrival and the hook make +3.5 attractive, but the injuries on the 49ers’ defensive front could eventually allow Stafford and the Rams offence to take control.

Our prediction: Los Angeles Rams 27-24 San Francisco 49ers

View the latest NFL odds.

All odds and markets are correct as of the date of publication.