Week 5 of the 2025 NFL season begins on Thursday with a matchup between the San Francisco 49ers and the Los Angeles Rams.These NFC West rivals are both 3-1 to open the year. Thursday’s game takes place at SoFi Stadium in Inglewood, California. Prime Video carries the Thursday Night NFL game.
The 49ers enter Week 5 coming off their first loss of the season, a 26-21 setback to the Jacksonville Jaguars.
The Rams began the 2025 NFL season with two wins. However, tey fell to the defending Super Bowl champion Philadelphia Eagles in Week 3. They bounced back in Week 4 with a 27-20 win over the Indianapolis Colts.
The 49ers, Rams, and Seahawks are all 3-1 in the NFC West standings heading into Week 5. The other team in the conference, the Arizona Cardinals, are 2-2.
Before we lay out the odds, preview, and prediction for the San Francisco 49ers vs. Los Angeles Rams in Week 5 2025 NFL action, check out our NFL betting odds and Super Bowl LX odds for 2026.
| Teams |  |  |  |
|---|---|---|---|
| San Francisco 49ers | +207 | +205 | +210 |
| Los Angeles Rams | -250 | -245 | -250 |
| SF 49ers +5.5 | -110 | -110 | -110 |
| LA Rams -5.5 | -110 | -110 | -110 |
| Over 47.5 Points | -107 | -110 | -110 |
| Under 47.5 Points | -113 | -110 | -110 |
The San Francisco 49ers opened the year 3-0, but behind those wins, concerns lingered. Those worries came to the forefront in Week 4 when the team fell 26-21 to the Jacksonville Jaguars. One of the big issues was the team’s defense. With star Nick Bosa out for the season with an ACL injury, the 49ers did not record a quarterback hit or sack. On top of that, the team allowed Travis Etienne to pick up 124 rushing yards, with an average of 6.5 yards per carry. The team does not have a lot of time to make adjustments on defense before Thursday night, but they must, or they will be in big trouble against the Rams.
San Francisco quarterback Brock Purdy missed two games (both wins) with an injured toe. He came back against Jacksonville to go 22-for-38 for 309 yards, with two TDs and two INTs. He said he felt good during the game, but on Sunday night, he reportedly told coach Kyle Shanahan that his toe was bothering him. Making that injury a little more troublesome is that backup Mac Jones was limited in practice last week with a knee sprain. With the top two QBs nursing injuries in a short week, that could be a problem for the 49ers.
The 49ers’ passing defense, which has been fairly strong this year, giving up an average of 165 yards per game, will be tested by the Rams.
The Los Angeles Rams offense is coming off a big game on Sunday. During the team’s 27-20 win over the Indianapolis Colts, quarterback Matthew Stafford went 29-for-41 with 375 yards passing to go with three touchdowns and zero interceptions. On the receiving front, Puka Nacua had 13 catches for 170 yards and one touchdown. Stafford is the No. 2 QB in the league with 1,114 yards, just five yards behind No. 1 Dak Prescott. Meanwhile, Nacau is the top receiver in the NFL with 503 yards and 42 receptions on 50 targets. If the struggling 49ers defense can’t contain Stafford and Nacau, the Rams could be in for another big day. The Rams have the No. 3 passing offense, averaging 267.5 yards per game.
The Rams have struggled on third downs this year. On Sunday, they went four-for-12. They need to improve their conversion rate.
The Rams’ defense needs to put more pressure on opposition quarterbacks. This is especially true, knowing that the 49ers could very well field a QB who is not at his physical best.
The Rams are a healthier and more productive team right now. With Bosa out and the quarterback situation a question for the 49ers, the pick is to go with Los Angeles to beat San Francisco.
The betting pick is for the Los Angeles Rams to beat the San Francisco 49ers at home on Thursday Night Football.
Defense will play a big role in this game, even with the 49ers not at their best on that side of the ball.
The betting pick is that the Los Angeles Rams and San Francisco 49ers will score under 47.5 points in Week 5 NFL action.
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