49ers vs. Rams Prediction, Odds, Spread, Injuries, Trends for NFL Week 5

Betting odds, pick and prediction for the San Francisco 49ers-Los Angeles Rams matchup in Week 5 of the NFL season.

Kyle Shanahan is 10-6 against Sean McVay in his coaching career. / Jayne Kamin-Oncea-Imagn Images

The Los Angeles Rams and San Francisco 49ers are both 3-1 in the 2025 season entering a crucial Week 5 matchup on Thursday Night Football. 

Los Angeles pulled out a huge win in Week 4 over the Indianapolis Colts, as Matthew Stafford found Tutu Atwell for an 88-yard score to take a 27-20 lead – which held up as the final.

San Francisco, on the other hand, dropped its first game of the 2025 season, as turnovers cost it late against the Jacksonville Jaguars. Brock Purdy did return from a turf toe injury and looked solid, but a late fumble ultimately cost San Fran a win.

Now, he faces a tough test against a Rams defense that has been one of the best in the NFL through the first four weeks of the season. 

There’s a ton of history between these teams, and Kyle Shanahan has gotten the best of Sean McVay in their meetings, going 10-6 all time (10-5 in the regular season). Still, his 49ers are three-point dogs in Week 5.

Here’s a breakdown of the odds, trends, key players to watch and my prediction for this NFC West battle on Thursday night. 

49ers vs. Rams Odds, Spread and Total

Odds via DraftKings Sportsbook

Spread

• 49ers +3 (+100)
• Rams -3 (-120)

Moneyline

• 49ers: +150
• Rams: -180

Total

• 47.5 (Over -105/Under -115)

49ers vs. Rams How to Watch

• Date: Thursday, Oct. 2
• Time: 8:15 p.m. EST
• Venue: SoFi Stadium
• How to Watch (TV): Prime Video
• 49ers record: 3-1
• Rams record: 3-1

49ers vs. Rams Betting Trends

• Kyle Shanahan is 10-6 against Sean McVay all time.
• The Rams are 3-1 against the spread this season. 
• The 49ers are 2-2 against the spread this season.
• The OVER is 2-2 in the Rams’ games in the 2025 season.
• The OVER is 2-2 in the 49ers’ game this season.
• The Rams are 2-0 against the spread as home favorites this season.

49ers vs. Rams Injury Reports

49ers Injury Report

• TBA

Rams Injury Report

• TBA

49ers vs. Rams Key Player to Watch

Christian McCaffrey, Running Back, 49ers

It hasn’t been a great season for McCaffrey running the football – he’s averaging just 3.4 yards per carry – but he has made an impact in the receiving game.

In Week 4 against the Jacksonville Jaguars, CMC caught six passes for 92 yards and a touchdown, leading the 49ers in receiving. With Brock Purdy back, it only makes McCaffrey more dangerous out of the backfield in the passing game.

The Rams allowed 76 yards on 17 carries to Jonathan Taylor (4.5 yards per carry) in Week 4, so it’ll be interesting to see if CMC can replicate a showing like that on the ground to help San Fran pull off an upset. 

49ers vs. Rams Prediction and Pick

These teams are two of the better defenses in the NFL, as they entered Week 4 at No. 4 (San Francisco) and No. 8 (Los Angeles) in EPA/Play on defense.

Now, they have a total that is nearing 50 in this Thursday night matchup, but I’m not sold on an offensive explosion in a short week.

So far this season, these teams are both 2-2 to the UNDER, and Thursday Night Football games have gone UNDER this number three times, finishing with 44, 45, 52 and 43 combined points.

Both of these teams would love to establish the run early, and while the Rams put up 27 points in Week 4, they benefitted from a few broken plays by the Colts secondary. 

On a short week, I wouldn’t be shocked to see this game go under, especially since Purdy has been at less than 100 percent to open this season. 

Pick: UNDER 47.5 (-115 at DraftKings)

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Odds refresh periodically and are subject to change.

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