Even after the Cardinals swept the 49ers in 2021, Arizona is more than a touchdown underdog on a neutral field in its first meeting of the season against San Francisco on "Monday Night Football."
It’s a battle between one of the best scoring defenses and one of the worst and the Cardinals' offense might be without quarterback Kyler Murray and receiver DeAndre Hopkins, both of whom are questionable for the game in Mexico City. Arizona beat the Rams last week with Colt McCoy under center, and he will start again if Murray can’t go.
This game matters a lot for the NFC West race as the 49ers (5-4) are currently in second place in the division behind the idle Seahawks and can take the top spot with a win this week. The Cardinals (4-6) are in third place and are just trying to stay afloat. A victory would go a long way toward keeping their playoff hopes alive.
San Francisco is an 8.5-point favorite, which matches its largest spread of the year. It covered as an 8.5-point favorite against Seattle back in Week 2 and failed to cover an 8-point spread last week against the Chargers. On the year, the 49ers are 4-5 against the spread. The Cardinals are 5-5 and this is their largest underdog spot of the season.
49ers vs. Cardinals Odds
Moneyline: 49ers (-350) | Cardinals (+275)
Spread: 49ers -8.5 (+100) | Cardinals +8.5 (-118)
Total: 43.5 Over (-110) | Under (-110)
The 49ers' success this season has been on the back of its defense, which ranks eighth in DVOA. They allow the fourth-fewest points (18.1) and second-fewest rushing yards (82.7) per game. San Francisco is also one of the best teams in the league at getting to the opposing quarterback with 29 sacks on the year, tied for fifth.
Its offense is not nearly as stout, despite its many multi-faceted weapons. Kyle Shanahan’s squad ranks 12th in DVOA on that side of the ball and welcomed back Elijah Mitchell to the running back room last week. Between Deebo Samuel, Brandon Aiyuk, George Kittle and Christian McCaffrey, Jimmy Garoppolo has plenty of weapons to distribute the ball to and he pilots an offense that ranks 10th in passing yards per game (236.3).
As for the Cardinals, they rank 21st in defensive DVOA and 28th on offense. They have a negative point differential so far this season. Though Arizona is technically the home team, it’s fared much better away from State Farm Stadium the last two seasons, so perhaps the international trip will do it well.
The Cardinals are decent against the run as they allow 110.5 yards per game, ranking 10th in the NFL. Yet they are very porous against the pass and rank in the bottom 10 (247.1). Their passing and rushing ranks on offense are not impressive either, with or without their stars. Murray has actually been the team’s top rusher so far ahead of James Conner. The team’s lead back averages less than 4.0 yards per carry on the ground.
And though Hopkins has been great since his return from suspension, Arizona’s passing offense is still a far shot from the league’s elite aerial attacks even with complementary pieces like Rondale Moore in place. Either Murray or McCoy will be without receiver Marquise Brown and tight end Zach Ertz this week, which means San Francisco can devote even more attention to Hopkins.
The 49ers can and will win their matchups all over the field, which is why I’m comfortable taking them even with such a large line. Without the safety blanket of Ertz over the middle, San Francisco will struggle to move the ball and there’s little hope for Conner doing much up against this front. I don’t see Mitchell and McCaffrey running all over Arizona, which is why I like the under, but this should be a resounding win for the Niners.