Cardinals at 49ers odds, picks and predictions

Sept. 26, 2026Updated Sept. 27, 2026, 7:28 a.m. ET

The Arizona Cardinals (1-1) face the San Francisco 49ers (2-0) Sunday in Santa Clara, California. Kickoff from Levi’s Stadium is at 4:05 p.m. ET (FOX). Let’s analyze NFL odds around the Cardinals vs. 49ers odds and make our expert NFL picks and predictions for the best bets.

The Cardinals, after a 26-14 Week 1 win over the Los Angeles Chargers as 9.5-point road underdogs, were blown out in Week 2 at home 31-7 as 4.5-point underdogs by the Seattle Seahawks , with the Under (40.5) cashing. They managed only 151 total yards of offense and QB Jacoby Brissett passed for only 95 yards on 28 attempts, throwing a touchdown pass and an interception.

The 49ers blew out the Miami Dolphins on Sunday 35-13 as 13.5-point home favorites. QB Brock Purdy earned NFC Offensive Player of the Week honors with 2 TD passes and a rushing touchdown. The defense has allowed 20 points through two games.

The 49ers lead the all-time series against the Cardinals 38-31. They swept the season series last year and have won 6 of the last 8 meetings. They beat the Cardinals 41-22 in Arizona as 3.5-point favorites with the Over (48.5) cashing.

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Provided by BetMGM Sportsbook; access USA TODAY Sports Scores and Sports Betting Odds hub for a full list. Lines last updated Saturday at 7 p.m. ET.

Moneyline (ML): Cardinals +320 (bet $100 to win $320) | 49ers -425 (bet $425 to win $100)Against the spread (ATS): Cardinals +8.5 (-112) | 49ers -8.5 (-105)Over/Under (O/U): 48 (O: -108 | U: -110)Cardinals at 49ers key injuries

Cardinals

DL Roy Lopez (groin) questionableCB Max Melton (toe) questionableS Dadrion Taylor-Demerson (back) out

49ers

DE Nick Bosa (knee, calf) outWR Mike Evans (hip) questionableDE Romello Height (hand) outWR Demarcus Robinson (ankle) outDL James Thompson (ankle) out

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Cardinals at 49ers picks and predictionsPrediction

49ers 31, Cardinals 20

The Cardinals have lost 12 of 14 games with Brissett as their starting quarterback. They have lost 7 straight division games. Brissett is 0-5 against division opponents, all losses by at least 17 points.

While Arizona can hang with the 49ers offensively, they do not play well from behind, and the 49ers offense has been tremendous so far.

Purdy is 5-1 in his career against the Cardinals with 12 TD passes and a rushing TD.

Expect the Niners to improve to 3-0, but the spread will give you better value.

PASS.

As noted, the Cardinals’ last 5 games against the NFC West have been losses of at least 17 points, all with Brissett as the starter. Their last 6 losses, dating back to last season, have been ATS losses as well.

The 49ers have won by at least 20 points in both games this season.

BET 49ERS -8 (-118).

The 49ers have scored at least 28 points in both games they have played. The Over has cashed in 6 of these teams’ last 8 meetings.

BET OVER 48 (-108).

Best prop bet

Christian McCaffrey 125+ RUSHING AND RECEIVING YARDS (+180)

He has cleared 125 combined rushing and receiving yards in 3 of the last 4 meetings with the Cardinals, and the other one he just missed it with 121 yards. With multiple receivers hurt this week, the passing game will flow through him.

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