Jacksonville Jaguars Vs San Francisco 49ers Pick and Prediction for Sunday, September 28, 2025

By: Ricky Mackenzie Updated 09/26/2025, 01:01 PM ET

Jaguars Preview

Trevor Lawrence and the Jacksonville Jaguars will travel west to take on Mac Jones and the undefeated San Francisco 49ers at Levi’s Stadium. Experience the thrill of confident decision-making with our proven methods for selecting top free NFL picks. Jacksonville enters at 2–1 with growing confidence, while San Francisco looks to stay unbeaten despite a massive blow to its defense with Nick Bosa now out for the year.

Lawrence has thrown for 671 yards and four touchdowns but has also turned it over four times. Against a defense like San Francisco’s, even without Bosa, mistakes will be punished. Jacksonville’s offensive line will need to be sharp in protection, and the run game has to offer balance early to avoid third-and-long situations.

49ers Preview

Mac Jones has been solid, throwing four touchdowns to just one interception through three games. His ability to get the ball out quickly and manage the game has helped keep the offense ahead of the chains. Christian McCaffrey continues to carry the workload on the ground and should be featured heavily again.

The 49ers will have to adjust defensively without their All-Pro edge rusher, and that opens the door for Jacksonville to find more rhythm than most visitors. This game could come down to red zone execution, and whichever side limits penalties and turnovers in key moments will likely come away with it.

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Jaguars vs 49ers Pick

Nick Bosa’s injury shifts the balance just enough to keep this game tighter than expected. Jacksonville will hang around late, but San Francisco’s home field and run game should carry them across the finish line. Take the 49ers to get the win, but for the Jaguars to cover. Final Score Prediction, San Francisco 49ers win 24-21.