Week 2 preseason action continues tonight when the bruised San Francisco 49ers square off against the Los Angeles Chargers at SoFi Stadium on the 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 prediction and NFL picks expect L.A. starters to have a bigger impact — especially with Kyle Shanahan playing it safe on Aug. 20.
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.
Justin Herbert player prop: 25+ passing yards
With Justin Herbert set to play just one series against the 49ers, there's no reason to chase more than 25 passing yards from the Pro Bowl QB. But 25 is an attainable number given what we saw from both teams last week.
In the Chargers' opening drive of McDaniel's tenure as offensive coordinator, L.A. threw the ball six times, and Trey Lance passed for 34 yards. In the 49ers' opening defensive drive last week against the Titans, Cam Ward led a TD drive and also threw for 34 yards.
For Herbert to hit 25+ passing yards, he may only need two completions with the talented pass catchers he has and San Fran's defensive injuries.
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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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