Kyle Shanahan has led the franchise to 13 straight regular season wins. They have their first 3-0 start since 2019.
The Cardinals are still uncertain on when quarterback Kyler Murray will return from his ACL injury, but last week handed the Dallas Cowboys a slice of humble pie in the form of a 28-16 upset.
This game features two of the NFL's top rushers this season. San Francisco's Christian McCaffrey continues to show his excellence with a league-leading 353 yards with three touchdowns. For Arizona, James Conner is third in the league with 266 rushing yards and two touchdowns.
Last year, San Francisco won both games against Arizona with Brock Purdy going 15-of-20 for 178 yards and three touchdowns.
49ers vs. Cardinals odds, moneyline, over/under
Spread: 49ers (-14)
Moneyline: 49ers (-1000); Cardinals (+625)
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Lorenzo Reyes: 49ers 27, Cardinals 19
San Francisco looks very much like the most balanced team in the NFL. But Arizona has surprised by playing opponents tough, despite being in the middle of a rebuild. With that in mind, a two-touchdown spread is quite a big ask, even for the Niners, so I’m on the Cards to cover.
Tyler Dragon: 49ers 31, Cardinals 13
The Cardinals had a signature win versus the Cowboys last week that should lay the foundation of the culture Jonathan Gannon is trying to establish in Arizona. The Cardinals are in for a reality check this week, though. The 3-0 49ers are currently the most complete team in football.
Victoria Hernandez: 49ers 33, Cardinals 20
The 49ers are at home, have managed to stay healthy and have a few extra days rest since they played on Thursday last week. Along with their high-powered offense, five different defenders have registered a sack so far. James Conner has done his best keeping Arizona afloat, but last week's shocking upset won't be repeated.
Jordan Mendoza: 49ers 31, Cardinals 10
The 49ers might be the best team in the NFC in the young season. Arizona pulled off a stunner against Dallas, but it doesn’t feel like they can repeat that success this time around. San Francisco quickly puts this one away.
You can view the full list of USA TODAY's NFL expert predictions here.
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This article originally appeared on USA TODAY: Arizona Cardinals at San Francisco 49ers: Game predictions, picks, odds