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

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

• The Cardinals have lost each of their last eight games against opponents on a winning streak.
• The 49ers have won each of their last four home games in September.
• The favorites have covered the spread in each of the 49ers’ last four games.
• The Cardinals have failed to cover the spread in four of their last five Week 3 games against NFC opponents.
• The 49ers have won the first quarter in each of their last nine games in California.
• The Cardinals have lost the first half in 15 of their last 16 Week 3 road games.
• The 49ers have scored the first touchdown in each of their last six Sunday games as favorites.

Why the Arizona Cardinals will win

• The 49ers have lost each of their last seven Week 3 games against NFC West opponents.
• The road team has won seven of the Cardinals’ last eight Week 3 games.
• The 49ers have failed to cover the spread in each of their last nine home games following a win.
• The Cardinals have covered the spread in each of their last eight road games in September.
• The Cardinals have scored the first touchdown in eight of their last nine Sunday games played on the West Coast.
• The Cardinals have won the first quarter in three of their last four September games as underdogs.
• The 49ers have lost the first half in each of their last four Sunday games against teams that held a winning record.

Total Points Facts

• Each of the Cardinals’ last six September games as underdogs against NFC West opponents have gone UNDER the total points line.
• Eight of the 49ers’ last nine games against the Cardinals following a win have gone OVER the total points line.

San Francisco 49ers Player Prop Facts

• Brian Robinson has recorded 43+ rushing and receiving yards in nine of his 10 previous appearances with his team as a home favorite against NFC opponents.
• Russell Gage has scored at least one touchdown in three of his last four appearances in home day games against teams with a winning record.
• Ricky Pearsall has recorded 56+ receiving yards in each of the 49ers’ last four games.
• Brian Robinson has recorded 33+ rushing yards in each of his six previous appearances against NFC West opponents.
• Mac Jones has recorded 231+ passing yards in each of his five previous September home appearances.
• Mac Jones has recorded 22+ completions in each of his five previous September home appearances.
• Heading into Week 3, Fred Warner ranks T1st in the league for fumbles recovered (1) this season.

Arizona Cardinals Player Prop Facts

• James Conner has recorded 89+ rushing and receiving yards in three of the Cardinals’ last four games as underdogs against NFC West opponents.
• James Conner has scored a touchdown in seven of the Cardinals’ last eight September games.
• Trey McBride has recorded 65+ receiving yards in each of the Cardinals’ last seven games played on the West Coast.
• Kyler Murray has recorded 32+ rushing yards in each of the Cardinals’ last four road games.
• Kyler Murray has recorded 260+ passing yards in each of the Cardinals’ last four games as underdogs.
• Kyler Murray has recorded 21+ completions in each of his 10 previous September appearances with the Cardinals as underdogs.
• Heading into Week 3, James Conner ranks T1st amongst qualified players for catch rate (100.0%) this season.

Matchup/League Facts

• 49ers – three different players have recorded 60+ receiving yards in a game this season – equal-most in the NFL, heading into Week 3.
• 49ers – three different players have recorded 70+ receiving yards in a game this season – equal-most in the NFL, heading into Week 3.
• Heading into Week 3, the Cardinals rank T1st in the NFL in 4th down percentage (100.0%) this season.
• Heading into Week 3, the Cardinals rank T1st in the NFL in Q1 win percentage (100.0) this season.

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.