The already banged-up San Francisco 49ers head south to SoFi Stadium in Los Angeles to take on the Los Angeles Chargers on Thursday at 10 p.m. ET (NFL Network).
With both teams playing their starters for at least a series, San Francisco is a 1.5-point road favorite; however, my 49ers vs. Chargers predictions and NFL picks expect Kyle Shanahan to be overly cautious, given his team is already dealing with a pile of injuries.
49ers vs Chargers prediction
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Who will win 49ers vs Chargers: Chargers moneyline
Although both the San Francisco 49ers and Los Angeles Chargers have announced they'll play many of their starters, neither team is expected to keep them in for more than a series.
Now, factor in the laundry list of injuries San Francisco is already dealing with — from Christian McCaffrey, Mike Evans, and George Kittle to Nick Bosa and Mykel Williams — and it's easy to buy into the "substation theory".
But the biggest injury for this specific game might be the rib fracture suffered by third-string QB Kurtis Rourke in the preseason opener.
With Brock Purdy's injury history and Rourke already out, Shanahan may not keep backup QB Mac Jones in long against the Chargers.
That means a lot of playing time for Adrian Martinez, who led San Francisco to six points last week against the Tennessee Titans (he had just a 66.2% adjusted completion percentage on a 7.2 average depth of target).
Meanwhile, the Chargers have Trey Lance against his former team, and even if revenge spots have been debunked by our Jason Logan, he and DJ Uiagalelei flashed their fit in Mike McDaniel's offense last week by putting up 27 points.
49ers vs Chargers Over/Under pick: Under 38.5
The preseason Under trend should continue in a game that likely sees both Martinez and Uiagalelei play at least a half each.
In Week 1 of the preseason, the Under was 12-4, and both these teams hit it. And with both teams already dealing with injuries on the O-line and at skill positions, there isn't much offensive depth to believe in.
But the defenses have real depth. The 49ers have an experienced second-string defense led by former NFL starters like Jack Jones and Nate Hobbs, and the Chargers have a flashy rookie duo in Akheem Mesidor and Genesis Smith surrounded by veterans like Bud Dupree.
The injuries hanging over both these teams right now should inform how quickly Shanahan and Jim Harbaugh pull relevant players.
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How to watch 49ers vs Chargers
| Location | SoFi Stadium, Inglewood, CA |
| Date | Thursday, Aug. 20, 2026 |
| Kickoff | 10 p.m. ET |
| TV | NFL Network |
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