49ers vs Rams NFL Week 5 TNF Best Picks

Week 5 of the 2025 NFL season will get underway on Thursday Night Football, as the Los Angeles Rams will play host to the San Francisco 49ers in a pivotal matchup in the NFC West. With the Rams beating the Colts last week and San Francisco suffering further injuries in a loss to Jacksonville, this game presents a chance for both teams to move into first place in the division.

Which team will come out on top and move to 4-1 on the season? Let’s get into our 49ers vs Rams best bets for TNF.

49ers vs Rams TNF predictions

• Pick #1: Los Angeles Rams -6.5 (-115) vs. San Francisco 49ers Click Here to Bet
• Pick #2: Over 46.5 (-110) Click Here to Bet
• Pick #3: Puka Nacua Anytime Touchdown Scorer (+100) Click Here to Bet

PICK #1: Rams -6.5 (-115) vs. 49ers

Even though both teams are 3-1 at the moment, they certainly feel like they’re going in different directions. After all, the 49ers just turned the ball over four times against the upstart Jaguars, and the offense has been ravaged by injuries to its wide receiving corps and offensive line, to say nothing of Brock Purdy’s injury that sidelined him for a few weeks. Therefore, even though Kyle Shanahan and company have historically had success against the Rams, Sean McVay’s group is healthier and playing better football on both sides of the ball heading into this contest. 

One could argue that Los Angeles should be 4-0 if not for a game against the Eagles, where the Rams blew a 19-point lead in the second half. The Los Angeles offense is easily a top 10 unit in the sport at the moment, with Matthew Stafford looking like one of the best quarterbacks we have. The dynamic duo of Puka Nacua and DeVante Adams is proving to be very difficult to contain on the outside. As long as the Rams continue to play mistake-free football (zero turnovers in a win over the Colts last week), they should be in a good position to win and cover on Thursday. 

PICK #2: Over 46.5 (-110)

Regardless of which team wins on Thursday, this game should be a close, high-scoring affair. As previously mentioned, the 49ers defense has been compromised due to the rash of injuries on that unit, and they’ll finally be facing an offense that can do real damage on the ground and through the air. Los Angeles is averaging nearly 400 yards per game, while sitting inside the top 10 in EPA per pass and EPA per play per SumerSports. 

On the other side, Brock Purdy is back under center for San Francisco. While the 49ers have been inconsistent on offense to this point, they still should be able to lean on Christian McCaffrey and produce against a Rams defense that is much weaker against the run (18th in EPA per rush allowed) than against the pass. Let’s take the Over in this NFC West clash. 

PICK #3: Puka Nacua Anytime Touchdown Scorer (+100)

Through the first four weeks in the season, Puka Nacua has arguably been the best wide receiver in the game, and he should be in a good position to succeed once again on Thursday.

The BYU product has been particularly unguardable, leading the NFL in receptions (42) and receiving yards (503) to this point. Nacua is clearly Stafford’s favorite target, and he should flourish against a 49ers defense that has faced Jacksonville, New Orleans, and Arizona in recent weeks. This is a massive step-up in class for San Francisco's secondary, and Nacua should benefit as a result.