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Arizona Cardinals vs San Francisco 49ers Prediction 9/21/2025 Today’s NFL Picks

Sep 14, 2025; New Orleans, Louisiana, USA;  San Francisco 49ers quarterback Mac Jones (10) passes against the New Orleans Saints during the second half at Caesars Superdome. Mandatory Credit: Stephen Lew-Imagn Images

Sep 14, 2025; New Orleans, Louisiana, USA; San Francisco 49ers quarterback Mac Jones (10) passes against the New Orleans Saints during the second half at Caesars Superdome. Mandatory Credit: Stephen Lew-Imagn Images

MATCHUP Cardinals Arizona 49ers San Francisco
Team Records 2-1 3-0
Where Levi's Stadium, Santa Clara, CA
When Sunday, September 21, 2025
Time 04:25 PM EDT
TV FOX

The Arizona Cardinals and the San Francisco 49ers meet in week 3 NFL action from Levi’s Stadium on Sunday. We will look at this from a betting perspective and determine the best bets for this game. Here’s an Arizona Cardinals vs. San Francisco 49ers prediction.

Arizona Cardinals Recap

The Arizona Cardinals come into this game looking to build on their 2-0 start after a 27-22 win over the Carolina Panthers in their last matchup. After this game, the Cardinals will head home for a game against the Seattle Seahawks.

Cardinals Looking To Remain Unbeaten

Kyler Murray has thrown for 383 yards, 3 touchdowns and an interception on 70.4% passing while Trey Benson leads the Cardinals in rushing with 83 rushing yards and James Conner has 73 rushing yards and a touchdown this season. Trey McBride leads the Cardinals with 12 catches for 139 yards while Marvin Harrison Jr. has 98 receiving yards and a touchdown. On defense, Budda Baker and Jalen Thompson each have a team-high 18 total tackles with Thompson logging a team-high 10 solo tackles. Calais Campbell also has a team-high 2 sacks so far this season.

San Francisco 49ers Recap

The San Francisco 49ers come into this game looking to add on to their 26-21 win over the New Orleans Saints last time out to improve to 2-0 this season as well. After this game, the 49ers will take on the Jacksonville Jaguars in a game at home.

49ers Looking To Start Home Opener Right

Mac Jones has thrown for 279 yards and 3 touchdowns on 66.7% passing while Brock Purdy’s thrown for 277 yards, 2 touchdowns and 2 interceptions on 74.3% passing. Christian McCaffrey has a team-high 124 rushing yards while also logging a team-high 15 receptions for 125 yards and a touchdown. Ricky Pearsall has a team-high 164 receiving yards while Jauan Jennings has 105 receiving yards and a touchdown. On defense, Fred Warner has a team-high 19 total tackles along with 11 solo tackles while Nick Bosa has a team-high 2 sacks.

Arizona Cardinals @ San Francisco 49ers Betting Trends: Week 3

Why the San Francisco 49ers will win

Why the Arizona Cardinals will win

Total Points Facts

San Francisco 49ers Player Prop Facts

Arizona Cardinals Player Prop Facts

Matchup/League Facts

Arizona Cardinals vs. San Francisco 49ers Prediction

I’m on the 49ers here. I get that it’s Mac Jones at QB1, and both teams have played the Saints so far but we’ve also seen Arizona face the Carolina Panthers and that might be the easiest two games you could have to start the season. I think that Kyler Murray’s going to be running for his life against this 49er defense, and I think that Mac Jones can keep up the gig for at least another week. I’ll roll with San Francisco here.

Chris Ruffolo's Pick: San Francisco -2.5

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