The 49ers, with Mac Jones at QB, host the 2-0 Cardinals on Sept. 21, aiming for a 3-0 start in a key NFC West clash.

The San Francisco 49ers host the 2-0 Arizona Cardinals in an NFC West showdown on September 21, 2025, at Levi's Stadium, wearing all-white throwback jerseys to stay cool in warm weather. With Brock Purdy out, Mac Jones starts at quarterback as the 49ers aim to begin 3-0. Christian McCaffrey remains a key offensive weapon, while the defense focuses on containing Kyler Murray and tight end Trey McBride. The 49ers lead in rushing defense and turnovers forced, though both teams are closely matched in yardage and scoring. The game streams on Fubo with regional restrictions, and betting is available via BetMGM.