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Matt O'Leary takes a look at Arizona Cardinals vs San Francisco 49ers and makes his predictions and picks. Can Arizona keep their hot streak alive?

NFL Expert Picks: Arizona Cardinals vs. San Francisco 49ers Predictions

After starting the year 2-0, the San Francisco 49ers have dropped their last two games to the Green Bay Packers and Seattle Seahawks. They’ve allowed 58 points over their last two games and have a bit of an issue now as Jimmy Garoppolo is dealing with a calf injury.

Jimmy G looks like a coin flip to play this week right now, which may be tough news as the 49ers head to Arizona to take on the undefeated Cardinals. The Cards are 4-0 coming off of a huge win over the Los Angeles Rams.

They have the number one offense in football, and defensively they’ve been more than capable holding opponents to 20 points or less in three of their four games. Let’s take a look at some Arizona Cardinals vs San Francisco 49ers predictions for this NFC West battle.

Arizona Cardinals vs. San Francisco 49ers Predictions

It’s taken a couple of years but it finally seems that Kliff Kingsbury has figured out the NFL. His team is first in both points for and yards and they’re averaging an insane 35 points per game through the first quarter of the season.

The biggest reason for the glow-up has to be Kyler Murray. In his third NFL season, he’s playing the best football of his career. He’s completing 76.1 percent of his passes for 318.3 yards per game a 9.5 yards per attempt and a 115.0 rating.

Plus, the offense isn’t all fed through DeAndre Hopkins. Sure, he still gets his targets with 25 in four games but Chase Edmonds, Christian Kirk, and A.J. Green all have 18 or more targets in the receiving game. They’re spreading the ball around which makes it harder on the opposing defense.

With the ninth overall defense to go along with their high-powered offense, they’re a very difficult team to beat. They’re third in the NFL with nine takeaways and are just on the outside of the top-10 in terms of passing yards against sitting at 886 which is good enough for 11th.

A big factor in this 49ers vs Cardinals predictions has to be the 49ers’ defensive struggles. Was Robert Saleh that big of a factor for them? Right now, they’re sitting at 22nd overall in the league. They have just nine sacks through four games and are getting pressure on just 21.8 percent of their pass rush reps.


That’s uncharacteristic for them in recent years. Plus on the offensive side of the ball, they’ve cooled off tremendously after Week 1. They hung 41 on the Lions and then followed it up with 17, 28, and 21 points over their last three games.

The ground game has just not been the same. They’re averaging just 3.9 yards per carry and have been decimated by injuries at the running back position. Usually, the run game has been the bread and butter of this offense but in 2021, it’s very clearly taken a step back.

I’m not sure if San Francisco has enough to keep pace with the offense of the Cardinals. They’ve given us no reason to believe that they can in three of their four games and defensively, they’ve just been downright bad.

Don’t let the big number at 5.5 scare you when making your Cardinals vs 49ers picks. Arizona is 3-1 against the spread this year with an average margin of victory of 13.8. San Francisco is just 1-3 against the spread and has an ATS +/- of -3.2.

The 49ers have been pretty solid in divisional games going 4-3 ATS since the start of 2020 but it’s not enough to get me off my Arizona Cardinals vs San Francisco 49ers prediction. Give me the Cardinals -5.5

Arizona Cardinals vs San Francisco 49ers Picks

Cardinals -5.5 (-108)


Article Author


OddsChecker sports writer Matt O'Leary brings experience sports betting advice to the OC staff. You may recognize Matt from his popular New York Jets youtube channel, but his vast knowledge of sports and betting goes well past the boundaries of New York.

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