Kyler Murray, already selected for the Pro Bowl twice in his career, helped the Cardinals sweep San Francisco last season, using his “squirrel”-like elusiveness as highlighted by former 49ers defensive tackle DeForest Buckner. To make matters worse for the San Francisco 49ers, their running game hasn’t found its footing in 2025; inside runs are collapsing without success, and their offense isn’t hiding that weakness, which is exactly what the Cardinals’ defensive linemen, like Calais Campbell, are going to take advantage of.

That’s the concerning challenge. Insider Grant Cohn recently laid out openly how the 49ers have historically struggled to contain Murray in the pocket. “On the other side, they struggle against Kyler Murray. They have had trouble keeping him in the pocket. And when he gets outside the pocket, they’re at his mercy,” Cohn explained. He also questioned the Niners’ defensive line depth, pointing out that it consists of young players like Mike Williams and Alfred Collins, who may be vulnerable in the fourth quarter after battling Murray’s speed and Arizona’s run-heavy approach in high heat.

“It’s a team that uses a lot of tight ends. They’re going to run the ball and put a lot of pressure on the Niners’ defensive line, which has been solid at times, but it’s a bunch of rookies. It’s one thing to do well against the Saints, who aren’t really trying to run the ball, but the Cardinals are, and it’s going to be 85 degrees. What’s Mike Williams, what’s Alfred Collins going to look like in the fourth quarter after they’ve been chasing around Kyler Murray and James Conner all day?

The greater threat may not even be Murray through the air. His legs remain lethal. In last October’s matchup, he raced 50 yards for a touchdown on the second snap of the game, setting the tone for what became a game-winning drive capped by a TD pass in the fourth quarter. In their Week 18 meeting, he scored a career high with four TD passes against a wobbling 49ers defense.

“So, it’s probably going to be a close game. And if the Niners let Kyler Murray out of the pocket one time in the fourth quarter, if their run defense falls apart, if their defensive line falls apart, it’s a close game. They could lose,” Cohn added.

Even Linebacker Fred Warner shared a similarity: “Kyler is always a really tough player to go against. One of the best in this league.” Arizona is off to its best start since 2021, with Murray guiding the offense to back-to-back wins over New Orleans and Carolina. “I felt we played better,” Murray said about Week 2. Meanwhile, the 49ers face quarterback uncertainty.

Is Kyler Murray posing a threat to Robert Saleh’s secondary?

While DL Nick Bosa added that he loved the game plan this week, there’s a strong warning for Saleh. Columnist Lowell Cohn echoed the concern: “And the Niners are not particularly better than they were last season.”

Murray can and likely will target the 49ers’ secondary, starting cornerback Renardo Green. As Grant Cohn explained, “There’s more. They haven’t really faced a great offense yet, but that young quarterback, Renardo Green, has been getting torched. He gave up a long catch to the Saints, gave up a long catch to the Seahawks, and now he has to face Marvin Harrison Jr. You’ve heard of his dad. He was the fourth pick in the draft last year. I don’t know if he was necessarily worth it—if his name was Marvin Smith, he might not have been the number four pick—but they’re going to go after Renardo Green deep down the field. 

The Niners’ most glaring vulnerability remains pass coverage at safety. Seattle ignored it entirely; New Orleans did not, resulting in three touchdowns allowed. So far this season, the Cardinals haven’t leaned heavily on Marvin Harrison Jr., with just 11 targets and seven catches totaling under 100 yards across two games. But the 49ers’ secondary could give Arizona an opening. The Cardinals have already found success attacking young corners, like New Orleans’ Kool-Aid McKinstry, and they’ll likely look to exploit similar mismatches.

“Marvin Harrison Jr. is the only wide receiver they really throw to on their team. The other guys are not factors.”

If Green gets beaten downfield, Saleh may have to adjust by letting Deommodore Lenoir play against Harrison Jr., a move that could shift the dynamics of the defensive scheme. The question now is whether Arizona has the way to test San Francisco’s safeties in a way that forces Murray to attack the deep ball or tight-window throws.