49ers, Mac Jones Without Top Playmaker Week 3 vs. Cardinals

The Arizona Cardinals (2-0) head to Levi’s Stadium to take on the San Francisco 49ers (2-0), who are still adjusting to life with Mac Jones under center while Brock Purdy deals with toe and shoulder issues.
Arizona enters this one oozing with confidence after sweeping last year’s series, while the Niners are focused on keeping the wins coming despite being without their QB1. Kickoff is set for Sunday, September 21 at 4:25 p.m. ET on FOX.
The 49ers already placed offensive lineman Spencer Burford on injured reserve, and wideout Jauan Jennings will sit this one out to nurse his ankle injury. The Niners elevated depth at wideout (Malik Turner) and quarterback (Adrian Martinez) heading into this one. Here’s a look at the players who will be inactive for Sunday’s matchup against the Cards:
WR Jauan Jennings
QB Brock Purdy
RB Jordan James
DL Jordan Jefferson
LB Nick Martin
WR Jordan Watkins
A Look Back at the Recent Series Between the 49ers & Cardinals
The recent history between these teams has been streaky. San Francisco swept both games in 2023, outscoring Arizona by a combined total of 80–45.
Arizona struck back in 2024 with a surprising sweep of their own, including a season finale where Kyler Murray and company lit up the Niners for 47 points. The all-time series leans narrowly San Francisco’s way at 36–31, but Arizona currently has the momentum with two straight wins.
The Cardinals are 7-4 at Levi’s Stadium, and with both a passing and rushing TD, Murray would have at least one passing and one rushing TD in all four of his career starts on the Niners’ home turf.
The Mac Jones Factor
Jones looked sharp in his first 49ers start, throwing three touchdowns without an interception in last week’s win over the Saints.
How Jones handles pressure from Arizona’s defensive front will be crucial. He’ll likely lean on Christian McCaffrey as both a runner and receiver to ease the burden.
“I played against them a few years ago. It’s a new scheme and some similar players, but they do a great job disguising coverage and got a lot of good players on the back end,” Jones said about the Cardinals this week.
“Obviously, their defensive line is explosive. I’ve been very impressed with them on film this year and obviously last year too. So they got play makers, they try to confuse the quarterback and they do a good job of that.”
Robert Saleh, 49ers Defense Ready to Take on the Kyler Murray Challenge
On the flip side, Murray has been a thorn in the 49ers’ side in recent starts. He put together two big performances against San Francisco last season, using his legs to extend plays and create explosives.
Keeping him contained will be the top priority for Nick Bosa, Fred Warner and the rest of the defense. Expect the Niners to employ a spy on passing downs and emphasize disciplined rush lanes to prevent Murray from breaking contain.
“He is fast, he’s elusive. He’s a jitterbug,” 49ers defensive coordinator Robert Saleh said about Murray. “He is also a passer first. He’s not just looking to run. He is looking to buy some time to be able to put the ball in the air, but he’s as challenging as it gets.”
Ultimately, this game will likely be won by the QB who makes the fewest mistakes. If Jones continues his efficient play and the 49ers’ defense keeps Murray bottled up, San Francisco should regain control of the rivalry. But if Murray is allowed to create the kind of chaos he did last season, Arizona could very well extend its streak.
Either way, expect a tight divisional battle with big-play potential written all over it.