The San Francisco 49ers enter Sunday’s divisional matchup against the Arizona Cardinals with quarterback uncertainty dominating the headlines. Brock Purdy, who has been battling shoulder and toe injuries, is officially questionable, but head coach Kyle Shanahan has already indicated it’s “highly unlikely” the starter will take the field. Instead, Mac Jones—who led the Niners to victory in Week 2—will be under center at Levi’s Stadium, with Purdy only available in a backup or emergency capacity if healthy enough to dress.

Despite the quarterback shuffle, San Francisco remains a slight favorite at home. Oddsmakers list the 49ers at -2.5 on the spread and -130 on the moneyline, with Dimers’ predictive model giving them a 60% chance of victory after simulating the matchup 10,000 times. The Cardinals, led by Kyler Murray, are priced at +120 to pull off the upset, and their chances may hinge on whether playmakers like James Conner and rookie wideout Marvin Harrison Jr. can make explosive plays against a stout San Francisco defense.

The model’s projected score—49ers 23, Cardinals 21—underscores how tight this NFC West battle could be. Betting insights highlight San Francisco’s moneyline as the best play, while the total of 45 points leans slightly toward the under at 52% probability. With divisional stakes, star talent like Christian McCaffrey in the mix, and added drama surrounding Purdy’s status, Sunday’s game in Santa Clara has all the ingredients for a tense, closely contested clash.

Cardinals vs. 49ers betting preview

Explore the interactive widget below to view the current spread, total, and moneyline odds and probabilities for the Cardinals-49ers game at Levi’s Stadium.

This prediction and best bet for Sunday’s NFL matchup between the Cardinals and 49ers is from Dimers.com, a leader in sports betting predictions.

Check out all the important details on today’s game, as well as the best odds sourced from the top sportsbooks in the country.

Game details

The key information you need before the Cardinals vs. 49ers NFL game.

Teams: Arizona Cardinals vs. San Francisco 49ersDate: Sunday, September 21, 2025Kickoff: 4:25 p.m. ETLocation: Levi’s StadiumNFL standings: Current NFL division standingsNFL injuries: Check the latest updates to the official NFL injury reportOdds

The latest and best odds for the NFL showdown between the Cardinals and 49ers.

Spread: Cardinals +2.5 (-105), 49ers -2.5 (-105)Moneyline: Cardinals +120, 49ers -130Total: Over/Under 45 (-110/-110)

The odds and lines presented here are the best available from selected sports betting sites at the time of publication and are subject to change.

Expert prediction: Cardinals vs. 49ers

Using trusted data analysis and machine learning, the experts at Dimers have executed 10,000 simulations of Sunday’s Cardinals vs. 49ers game.

According to Dimers’ famous predictive analytics model, the 49ers are more likely to defeat the Cardinals at Levi’s Stadium. This prediction is based on the model giving the 49ers a 60% chance of winning the game.

Furthermore, Dimers predicts that the bookmakers have gotten it right and the Cardinals and 49ers each have a 50% chance of covering the spread, while the 45-point over/under has a 52% chance of staying under.

As always, these predictions and probabilities are correct at the time of publication but are subject to potential changes.

Cardinals vs. 49ers best bet

Our top pick for the Cardinals vs. 49ers Week 3 NFL matchup is to bet on the 49ers moneyline (-130).

This betting advice is formulated through world-class modeling and valuable wagering intelligence, designed to bring you the best possible plays.

Score prediction for Cardinals vs. 49ers

Dimers’ projected final score for the Arizona vs. San Francisco game on Sunday has the 49ers winning 23-21.

This expert prediction is based on each team’s average score following 10,000 game simulations, offering a glimpse into the potential outcome.

NFL player props: Sunday

NFL prop bets are a popular way to wager on Sunday’s game without necessarily betting on its outcome.

This article features the most likely first and anytime touchdown scorers for the Cardinals and 49ers, along with projected player stats.

Arizona CardinalsFirst touchdown scorer predictionsJames Conner: 11.9% probabilityMarvin Harrison: 7.7% probabilityTrey McBride: 6.3% probabilityAnytime touchdown predictionsJames Conner: 46.3% probabilityMarvin Harrison: 33.3% probabilityTrey McBride: 28.3% probabilityProjected box score leadersQB passing yards: Kyler Murray, 221 yardsReceiving yards: Trey McBride, 63 yardsRushing yards: James Conner, 56 yardsSan Francisco 49ersFirst touchdown scorer predictionsChristian McCaffrey: 15.6% probabilityRicky Pearsall: 6.6% probabilityJauan Jennings: 6.4% probabilityAnytime touchdown predictionsChristian McCaffrey: 57.6% probabilityRicky Pearsall: 30.6% probabilityJauan Jennings: 29.5% probabilityProjected box score leadersQB passing yards: Mac Jones, 221 yardsReceiving yards: Ricky Pearsall, 61 yardsRushing yards: Christian McCaffrey, 80 yardsNFL Week 3: Cardinals vs. 49ers

Get ready for Sunday’s action between the Cardinals and 49ers in Week 3 of the NFL season at Levi’s Stadium, which is scheduled to start at 4:25 p.m. ET. We emphasize that all of the NFL best bets and NFL predictions on this page are based on 10,000 data-driven simulations of the Cardinals vs. 49ers matchup, and they are accurate at the time of publishing to help you make better decisions when placing bets at online sportsbooks.

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