2025 NFL Week 5 49ers vs. Rams line, odds: Expert reveals pick for matchup on Thursday Night Football

Early control of the NFC West will be on the line when the San Francisco 49ers take on the Los Angeles Rams on Thursday Night Football. San Francisco dropped a 26-21 decision to Jacksonville, while Los Angeles pulled out a 27-20 win over Indianapolis on Sunday. The Rams (3-1), who are 0-1 in the conference, are 2-0 on their home field this season. The 49ers (3-1), who are 3-0 in the conference, are 2-0 on the road. San Francisco quarterback Brock Purdy (toe) has been ruled out, as have Jauan Jennings and Ricky Pearsall.

Kickoff from SoFi Stadium in Inglewood, Calif., is set for 8:15 p.m. ET. The 49ers lead the all-time series 78-71-3, including wins in each of the last five meetings. The Rams are 8.5-point favorite in the latest 49ers vs. Rams odds, while the over/under for total points scored is 43.5, after opening at 47.5. L.A. is at -455 on the money line (risk $455 to win $100), with San Fran at +350 (risk $100 to win $350).

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Before making any 49ers vs. Rams picks, you NEED to see which side SportsLine NFL expert Larry Hartstein is on, considering his mastery of picks involving the Rams.

A former lead writer for Covers and The Linemakers, Hartstein combines a vast network of Vegas sources with an analytical approach he honed while working for Pro Football Focus. Hartstein tied for 52nd place (out of 1,598 entries) in the 2022 Westgate Las Vegas SuperContest, going 53-34-3 ATS. He is coming off a down 2024 NFL season at SportsLine that puts him at 967-821 all-time on NFL sides and props (plus 13.8 units), including 593-518 ATS. Entering the 2025-26 season, he has been profitable in five of six seasons, going 659-564 ATS (plus $3,556 for $100 players). 

In addition, Hartstein has gone 25-10 on his last 35 picks involving the Rams, returning more than $1,400. Anyone who has followed him could be WAY UP!

Now, Hartstein has locked in another confident against-the-spread pick for 49ers vs. Rams.

We can tell you he's leaning Under on the point total, but he knows a crucial X-factor makes one side of the spread a MUST-BACK! You ABSOLUTELY need to see what it is before locking in any picks of your own.

So who wins 49ers vs. Rams on Thursday, and what x-factor makes one side of the spread hit HARD? ... Join SportsLine right now to see which side of the 49ers vs. Rams spread to back, all from the expert who is a blistering 25-10 on picks involving the Rams!

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