The Arizona Cardinals (2-0) visit the San Francisco 49ers (2-0) at Levi’s Stadium in Santa Clara for a Week 3 showdown, and USA TODAY’s panel of NFL experts have locked in their picks and predictions for the action. Here’s everything you need to know before kickoff on Sunday, September 21, including live updated odds and injury report news.
49ers vs. Cardinals live odds, moneyline, over/under
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49ers vs. Cardinals picks against the spread
Jordan Mendoza: Arizona Cardinals (+1.5)
The Cardinals had San Francisco’s number last season with a sweep, and it carries over. The injuries come back to hurt the 49ers badly.
Jon Hoefling: San Francisco 49ers (-1.5)
San Francisco may be out their top-two receiving options, but the Cardinals are without three members of their secondary with two more listed as questionable. Give me the home team 49ers.
Tyler Dragon: Arizona Cardinals (+1.5)
The 2-0 Cardinals are flying under the radar. A 3-0 start will make people start to notice.
Christopher Bumbaca: San Francisco 49ers (-1.5)
The Niners played better against the common opponent (Saints) and San Francisco is at home. Sometimes in these divisional matchups it is that simple.
Blake Schuster: San Francisco 49ers (-1.5)
I want to pick Arizona, I really do. But following the Cardinals’ inability to keep Carolina down in their own building last week, Kyler Murray needs to regain my trust.
Lorenzo Reyes: San Francisco 49ers (-1.5)
Kyle Shanahan facilitated things for Mac Jones with his game plan, and I expect more of the same. The Niners have the better roster and I think this is a really manageable spread for them. I love this spot.
49ers vs. Cardinals updated injury report
NFL Week 3 picks, predictions odds
USA TODAY NFL picks against the spread standings
NameWeek 2 Record2025 RecordChris Bumbaca10-617-13-2Tyler Dragon11-516-14-2Jon Hoefling10-616-14-2Lorenzo Reyes9-716-14-2Blake Schuster9-716-14-2Jordan Mendoza9-715-15-2
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