The front and back ends of the NFL schedule this year seem to be loaded up with divisional matchups. And, quite frankly, that’s a great way to do it. It’s when we care most about the games and when they are most meaningful. Guys are generally healthy early in the year, which makes for better games. And those last few games fighting for playoffs can often be great.

Unfortunately for the San Francisco 49ers, despite this being an early game, they are not super healthy. They’ll be down starting quarterback Brock Purdy as well as star tight end George Kittle. Can they overcome that and win this week’s matchup with the Arizona Cardinals? Let’s dig into the information at hand to figure that out!

Even if you just want to see the Cardinals vs. 49ers odds and have Cardinals vs. 49ers picks of your own, don’t forget to scroll down at the end to see how you can scoop up a $1,500 BetMGM Sportsbook sign-up bonus! 

 

 

 

Cardinals vs. 49ers Predictions For NFL Week 3, Sunday 4:25 PM ET

Given that they are both in the NFC West, these teams play at least twice a year - more if they were to ever meet in the playoffs (they haven’t). The 49ers had been getting the best of the Cardinals winning both games in the 2022 and 2023 seasons. But the Cardinals flipped the script a bit last year winning both matchups. 

So far the Arizona Cardinals are undefeated. But their competition hasn’t been stiff. They knocked off the Saints on the road 20-13 in Week 1. Then beat the Carolina Panthers at home 27-22 in Week 2. The 49ers are also undefeated after beating the Seahawks 17-13 and the Saints 26-21, both on the road.  

Arizona Cardinals: Jonathan Gannon Finally Has His Defense

The Cardinals invested heavily in the offense in previous years. Obviously they paid Kyler Murray big money. Trey McBride was a second-round pick who was paid handsomely as well. Then, they turned around and took the first WR off the board in 2024 in Marvin Harrison and the second RB off the board in Trey Benson. That’s to go along with veteran James Conner.

This year, head coach Jonathan Gannon finally got his turn to build his defense. They actually used their first five picks of the 2025 NFL draft all on defense with Walter Nolen, Will Johnson, Jordan Burch, Cody Simon, and Denzel Burke. We’ve yet to see Walter Nolen, as he has started the season on the PUP list which requires him to miss four games. That said, the defense has already looked better than previous year. 

San Francisco 49ers: The Injury Bug Hits Early

If we had guessed that the 49ers would suffer a major injury early, we probably would have guessed Christian McCaffrey. But he seems healthy and he’s been used heavily. It’s been quarterback Brock Purdy and George Kittle that are missing games. With Bradon Aiyuk on the IR and Jauan Jennings battling through injuries, it’s taken a lot of heart for this team to start 2-0.

The 49ers defense has been solid, as they often are. Through two games they rank top five in overall DVOA per FTN Fantasy which suggests they are a well-rounded unit vs both the pass and the run. They too used their first round pick on a pass-rusher with Mykel Williams to go opposite Nick Bosa. And Fred Warner is always roaming around the middle, wreaking havoc. 

 

 

 

Cardinals vs. 49ers Odds, Spreads, Total & Betting Lines

As promised, the latest Cardinals vs. 49ers odds can be found below courtesy of BetMGM Sportsbook:

 

 

 

Cardinals vs. 49ers: Cardinals +2.5  (-105 at BetMGM Sportsbook)

Sure, the Cardinals probably should have destroyed the Saints and the Panthers. Instead, they merely won those games without covering the spread. But this team looks different than years past as it’s not just the offense producing this time around - the defense is actually holding up their end of the deal. 

The Cardinals have actually averaged 24.1 points per game with Kyler Murray as the starting quarterback. That’s right there with the Bengals averaging 25.3 points per game with Joe Burrow as the starter. He has all the weapons in place to make things happen here with James Conner, Trey McBride, and Marvin Harrison. Unlike the Bengals, they might actually have a defense now.

If this were Brock Purdy, George Kittle, Brandon Aiyuk and the normal cast of characters, it might be a different story. But this 49ers team is missing too many key pieces to lean on. We might have even gone with the moneyline but we can actually get the Cardinals with 2.5 points at only -105 on BetMGM. So we’re going to play it safe and take the points.

 

 

 

Cardinals vs. 49ers Injury Report & Latest News

Finally, let’s take a quick look at the projected starting lineups for both teams heading into tonight’s matchup:

Arizona Cardinals

San Francisco 49ers

 

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