49ers vs. Rams Prediction: San Francisco Wins a Defensive Battle

The San Francisco 49ers and Los Angeles Rams open the 2026 NFL season tonight in Melbourne, Australia, in the first regular-season NFL game played in Australia. The Rams enter as 3.5-point favorites, but I’m going against the odds and taking San Francisco to pull off the upset. 

My prediction: 49ers 21, Rams 13

The Rams’ defense deserves plenty of respect. With Myles Garrett now in Los Angeles and a talented group surrounding him, the Rams should make life difficult for Brock Purdy and the San Francisco offense.

However, I believe the difference in this game will be San Francisco’s defense.

The 49ers are getting Nick Bosa back for the opener, while Fred Warner and Dre Greenlaw give San Francisco a much stronger defensive foundation. Bosa has been confirmed to play despite his limited preparation during training camp.

I expect San Francisco to make life difficult for Matthew Stafford, Puka Nacua and Davante Adams. The Rams have plenty of firepower, but I don’t think the 49ers will allow them to consistently connect on explosive passing plays.

Another factor I like for San Francisco is the preparation for Australia. The 49ers arrived nearly a week before the game, while the Rams traveled much later. That could become important in the second half if fatigue starts to set in. 

The Pick: 49ers 21, Rams 13

I think this is a low-scoring, physical NFC West battle. The Rams’ defense keeps them in the game, but San Francisco’s defense ultimately shuts down the Rams’ receiving game and gives Brock Purdy enough opportunities to win it late.

49ers pull off the upset in Australia.