49ers vs. Chargers Prediction: Preseason Week 2 Picks and Odds

The 49ers and Chargers run it back for the second straight summer, this time at SoFi Stadium as both teams tune up for Preseason Week 2. San Francisco enters at 0-1 after resting most of its starters in a 19-13 loss to Tennessee, while Los Angeles is 1-0 following a preseason-opening win. Neither record means much in August, but the buildup to Thursday night carries real intrigue: Kyle Shanahan is finally unleashing several first-teamers, and Justin Herbert is set to debut in Jim Harbaugh and Mike McDaniel’s new-look offense.

Herbert’s Offensive Debut Headlines a Loaded Night

Justin Herbert is expected to play roughly a series before handing things off to Trey Lance, who impressed by playing three quarters in the Chargers’ preseason opener, and then DJ Uiagalelei. It’s the first live look at Herbert running McDaniel’s system, and with Ladd McConkey and Quentin Johnston both trending toward game action after sitting out or being limited in Week 1, the Chargers’ skill talent should be on full display early.

Brock Purdy is also expected to make his 2026 preseason debut for San Francisco after Shanahan held him out of the opener. Purdy will work behind a line anchored by Trent Williams for at least a series, throwing to Deebo Samuel and a receiving corps trying to establish rhythm early in camp. San Francisco’s depth chart lists Purdy atop Mac Jones, with Kenny Pickett-era question marks behind him no longer part of the equation.

Two Teams Built to Win Now

Both rosters carry legitimate playoff aspirations, which is exactly why the “starters play a series or two” approach matters. On defense, the Chargers counter with one of the more physical fronts in the league: Khalil Mack and Tuli Tuipulotu anchor the edge, with Derwin James Jr. and Elijah Molden patrolling the back end. San Francisco will lean on Fred Warner at linebacker and Deommodore Lenoir in the secondary, though Nick Bosa remains on a gradual ramp-up from knee tendonitis, opening reps for Keon White and rookie Grayson Halton.

The line has moved throughout the week, with most books now installing San Francisco as a slight favorite (-1.5) after Chargers -1.5/-2 opened the market, and the total sitting in the high 30s, in the 38.5-to-39.5 range depending on the shop. That kind of number for a preseason game says plenty about how much starter snaps are expected here relative to a typical August tune-up.

Beyond the quarterbacks, special teams and depth battles matter just as much. Cameron Dicker has already flashed for Los Angeles after a solid preseason debut, and the Chargers’ return game with Derius Davis gives them an edge in field position if the game stays tight into the second half, which is often when backups take over and things get sloppy in a good way for bettors watching game flow.

Prediction and Best Bet

Expect a lively first quarter followed by the usual preseason unraveling once the backups take the field. Herbert and Purdy both operating behind largely healthy lines should produce enough early rhythm to push this game past a clean, low-scoring stalemate, even with backups mixing in resulting in some sloppy execution later.

• Prediction: Chargers 23, 49ers 20
• Best Bet: Over the total

With Herbert, McConkey, and Johnston expected to see the field early alongside Purdy and Samuel doing the same on the other sideline, there’s enough first-half firepower to clear a total that’s already been bet up slightly from its opening number, making the over the more appealing angle in a game where backups typically pad the score late.