49ers vs. Rams Prediction, Spread, NFL Week 1 Picks – Thursday, September 10

The San Francisco 49ers and Los Angeles Rams open their respective campaigns in an unusual setting, traveling all the way to Australia for Netflix’s NFL Melbourne Game. The Rams come in as 3.5-point favorites over the 49ers on PrizePicks, with the outing kicking off at 8:35 p.m. ET on Thursday night.

For the Rams, it’s Super Bowl or bust as they enter the season with a stacked roster on both sides of the ball. They’re the favorites to lift the Lombardi Trophy, returning a 5x payout to win the title on PrizePicks.

The 49ers also hope to be contenders, but injury and age concerns paint a murkier picture. There could be a wide range of outcomes depending on whether their key pieces can remain upright and productive.

Below, we’ll break down our 49ers vs. Rams prediction and picks for Thursday’s NFL game, including the spread, over/under, and PrizePicks player projections for Week 1.

Make your 49ers vs. Rams picks for Week 1 on PrizePicks!

{{nfl_offer_banner="/style-system/ui-components-playbook"}}

49ers vs. Rams Prediction, Spread, Over/Under for Week 1 – Thursday, September 10

The Rams came just short of reaching last season’s Super Bowl, falling to the Seattle Seahawks in the NFC Championship Game. 

Los Angeles was already well-equipped to make another deep run, returning an offense led by last year’s MVP, QB Matthew Stafford. The Rams’ offense put up the second-most EPA/play (0.149) and boasted the highest success rate (52.2%) in 2025, per RBSDM.

However, with a limited championship window left for the 38-year-old Stafford, the Rams decided it wasn’t enough to solely ride this high-flying offense and decided to significantly bolster the other side of the ball. 

As you likely know by now, the Rams acquired EDGE Myles Garrett and CB Trent McDuffie via trade, signed CB Jaylen Watson, and – because that wasn’t enough – also enticed old friend DT Aaron Donald to come out of retirement.

Donald didn’t make the trip to Melbourne, but the other three should help enhance a defense that was already a respectable seventh in both defensive EPA/play (-0.069) and success rate (41.8%) last year.   

It’s safe to say these Rams are going to be a handful all year.

San Francisco’s offense was sixth in EPA/play (0.091) and third in success rate (48.5%) in 2025, and it should once again be a potent unit with Kyle Shanahan pulling the strings.

However, the Niners will also be counting on significant production from RB Christian McCaffrey, WR Mike Evans, and TE George Kittle, who are all 30 or older. All three have already popped up with minor ailments during training camp. 

McCaffrey is also coming off a year when he led the NFL in touches (413), and it’s no secret he’s suffered several lengthy injury stints over his career. Star LT Trent Williams is still performing at a Pro Bowl level, but he turned 38 this summer, too.

Defensively, the 49ers’ advanced metrics were unfavorable, as they ranked 24th in EPA/play (0.070) and 30th in success rate (48.4%).    

This is a team that won 12 games last year and could still have a dangerous offense in 2026. However, it may be a boom-or-bust kind of season depending on how the roster holds up.

49ers vs. Rams Spread, Over/Under for Week 1 – Thursday, September 10

The Rams enter Thursday’s game as 3.5-point favorites against the 49ers, returning a 1.47x payout on PrizePicks if they win outright.

Play the 49ers vs. Rams spread or over/under on PrizePicks Team Picks.

Payouts show potential returns on correct Team Picks predictions. A 2x payout returns $200 on a $100 entry. Lower multipliers reflect outcomes users are picking as more likely. Payouts are live as of writing and subject to change. 

49ers vs. Rams Prediction on Spread – 9/10/26

Here are the key stats and trends behind our 49ers vs. Rams prediction on the spread for Thursday, September 10.

• The Rams bring back an offense that led the league in points per game (30.5) and yards per game (394.6). The defense could also be scary after adding Garrett, the Defensive Player of the Year, and revamping their secondary.
• The 49ers’ defense produced the third-worst pressure rate (16.7%) last year, per Pro Football Reference. It also ranked 29th in pass rush win rate, according to ESPN. 
• Adding DT Osa Odighizuwa this offseason should help the defensive line, but EDGE Nick Bosa will be the key to this pass rush, and he’s returning from a torn ACL. The unit has already lost DT Alfred Collins for the year, and EDGE Sam Okuayinonu was placed on IR.  
• While PFF ranks the 49ers’ linebacker group first in the NFL, the defensive line and secondary come in as bottom-half units.  
• As most teams would do, the 49ers arrived early in Australia to acclimate to the time difference. However, the Rams took an entirely different approach by flying in the day before the game. While that might seem reckless, Los Angeles used this strategy for their London game last season and went on to beat the Jaguars 35-7.
• Although they’re traveling a farther distance this time around, some experts still see this putting the Rams players in a better position to succeed.    

Make your 49ers vs. Rams picks now for Thursday’s NFL game.

49ers vs. Rams Picks, Player Stats for PrizePicks for Week 1 on PrizePicks: 9/10/26

Here are the top 49ers vs. Rams picks to target on Thursday, September 10. Today’s NFL picks for PrizePicks include RB Blake Corum, RB Christian McCaffrey and WR Mike Evans.

Rams RB Blake Corum vs. 49ers: 44.5 Rush Yards

• Corum was a popular sleeper pick in fantasy football this offseason due in part to positive offseason reports suggesting he could be in closer to a 50-50 split with RB Kyren Williams.
• From Week 7 onward last season, Corum began to see more consistent work, averaging 10.5 carries and 53.6 rushing yards over his last 11 games. He logged double-digit carries in seven of those weeks.
• Per Pro Football Focus, Corum ranked 12th in breakaway percentage (30.6%) among RBs with at least 100 rush attempts in 2025.
• In that same sample, Corum was first in EPA/rush (0.09), according to SumerSports.
• Corum averaged 5.1 yards per carry last year compared to 4.8 per carry for Williams.

Add Blake Corum to your PrizePicks lineup now.

{{nfl_offer_banner="/style-system/ui-components-playbook"}}

49ers RB Christian McCaffrey vs. Rams: 59.5 Rush Yards

• Last season, McCaffrey averaged just 3.9 rushing yards per attempt, well below his career average (4.6).
• CMC produced a 17.8% breakaway rate, ranking 38th out of 49 RBs with at least 100 carries. 
• The Rams were first in run stop win rate in 2025.
• In two games against the Rams last year, McCaffrey averaged 2.6 YPC in Week 5 and then 2.5 in Week 10. He failed to crack 60 rushing yards in either week.

Add Christian McCaffrey to your PrizePicks lineup now.

49ers WR Mike Evans vs. Rams: 6.5 Rec Targets

• Evans dealt with multiple injuries throughout training camp, but he downplayed any concerns and ultimately wasn’t listed on this week’s injury report. He’s expected to be the WR1 in this offense.
• Evans has averaged 8.5 targets per game over his 12-year career. Last year with Tampa Bay, he averaged 7.8.
• In 2025, he had 7+ targets in six of his eight contests.
• The veteran wideout’s main competition for targets will be Kittle, WR Deebo Samuel, and WR De'Zhaun Stribling. Kittle is returning from a torn Achilles, Samuel isn’t expected to be an every-down player, and Stribling is a rookie making his NFL debut.

Add Mike Evans to your PrizePicks lineup now.

Make 49ers vs. Rams Picks on PrizePicks

We’re getting a unique international game on Thursday as the San Francisco 49ers take on the Los Angeles Rams in Melbourne, Australia. Which NFC West team opens the season with a win?

Don't wait until kickoff — make your 49ers vs. Rams picks on PrizePicks now for Week 1 and earn real money if you're right.

Pick players, predict More or Less on their stats, and cash in if you’re right. With Team Picks, you can make predictions on NFL game winners, spreads, and over/unders, now available in 36 states.

Stay locked in on Playbook for daily NFL news, picks, analysis, and more all the way through Super Bowl LXI.