The San Francisco 49ers head to Arizona for a matchup with the Cardinals in a game that could mark a turning point in their season. With Brock Purdy and Ricky Pearsall returning to the lineup, the offense will finally be at full strength, and the team will look to move to 4-1 in the division. Here is our prediction for the Week 11 matchup.
49ers vs. Cardinals Week 11 Matchup Preview
The first meeting between these teams ended dramatically for the 49ers, with a game-winning drive led by Mac Jones and closed out by an Eddie Piñeiro field goal as time expired. In that matchup, Jones started for San Francisco, and Kyler Murray was under center for Arizona.
This time, the landscape is different. The 49ers get Purdy back, while the Cardinals placed Murray on injured reserve to recover from a foot injury. Jacoby Brissett will make his fifth start of the season, and the offense has looked more efficient with him. There is even a chance he keeps the job when Murray returns.
That means this rematch will have a completely new feel. We should expect a very different game than what we saw in Week 3, even though Arizona is still dealing with familiar issues. The Cardinals will be without key players, including cornerback Will Johnson, linebacker Baron Browning, and wide receiver Marvin Harrison Jr.
The 49ers, meanwhile, have only one questionable player, cornerback Deommodore Lenoir, who is dealing with a calf issue. The team elevated Eli Apple, a sign that Lenoir might sit after missing Friday’s practice. Beyond that, this is the healthiest San Francisco offense has been all season.
The 49ers Will Win If…
Kyle Shanahan’s offense will finally be at full strength. Purdy, Pearsall, George Kittle, Christian McCaffrey, and Jauan Jennings have played only one whole drive together this season, back in Week 1 against the Seattle Seahawks. Even with all the injuries along the way, the 49ers still rank ninth in the PFSN Offense Impact Meter with a score of 81.5.
Arizona’s defense sits at 17th in the PFSN Defense Impact Meter and struggled last week against Seattle, giving up 30 of the Seahawks’ 44 points. Shanahan is expected to target a depleted secondary and use Pearsall’s return to dictate tempo and reestablish the offensive rhythm.
Defensively, even without three major pieces in Nick Bosa, Mykel Williams, and Fred Warner, the 49ers face a Cardinals team missing its top receiver and likely to struggle with Christian McCaffrey in space, especially on routes out of the backfield.
The Cardinals Will Win If…
In the two games he played this season, Purdy was a turnover machine, throwing two interceptions in each appearance and adding a crucial fumble against the Jacksonville Jaguars that sealed the Week 5 loss.
Arizona forced three turnovers against the Seahawks: Two fumbles and one interception. The 49ers have the second-worst turnover differential in the NFL in 2025 at minus eight, ahead of only the New York Jets, who sit at minus eleven. If Arizona can create turnovers, San Francisco could fall into a negative spiral during the game.
San Francisco’s defensive line is one of the least effective in generating pressure. It is tied for the fewest sacks in the league with just twelve, matching Jacksonville and the Baltimore Ravens. Brissett can attack the middle of the field with Trey McBride, taking advantage of the fact that the 49ers could not contain the Los Angeles Rams’ tight ends in Week 10.
Prediction
The 49ers will have a different offense than in previous weeks, and explosive plays could start showing up more often again. Arizona is not coming into this week with a strong defense, and the absence of Johnson and Browning could make a real impact. San Francisco wins 30-21 with a solid game from Purdy.
