Cardinals vs. 49ers Prediction, NFL Week 3 Odds & Picks (9/27)

Fact checked at 5:50 PM ET, Sep 26, 2026

Odds as of Sep 26, 5:30 PM ET

San Francisco has done everything asked of it so far. The 49ers are 2-0 straight up and against the spread, level with Seattle atop the NFC West, after a 27-7 win over the Rams in Melbourne, Australia, on Thursday, Sep 10, and a 35-13 win over Miami last Sunday. Arizona (1-1) won 26-14 at the Chargers as a 9.5-point underdog, then lost 31-7 at home to Seattle. Kyle Shanahan faces another of his former assistants in new Arizona coach Mike LaFleur, and the 49ers swept last season's meetings, 16-15 at home and 41-22 in Arizona.

This week's injury news mostly went against San Francisco. Nick Bosa strained a calf before practice Thursday and will miss multiple weeks, pass rusher Romello Height (hand) is out, receiver Demarcus Robinson (ankle) went on injured reserve Saturday, and Mike Evans (hip) is questionable after missing two practices and returning on a limited basis Friday. The 49ers kept Bosa and Height off injured reserve for now and called up three defensive linemen from the practice squad. Arizona placed starting cornerback Will Johnson (neck) on injured reserve, though Garrett Williams (Achilles) practiced fully Friday, carries no designation and is expected to make his season debut.

The line has come Arizona's way, at least compared with the look-ahead number. San Francisco was an 11.5-point favorite on the look-ahead line and is now -8.5 (-108) at the consensus, where it has sat since the Week 3 lines opened. The moneyline has dropped from -650 to -440, with Arizona at +340. The total opened 46.5 and sits at 47.5.

Kickoff is Sunday at 4:05 PM ET at Levi's Stadium in Santa Clara, on FOX.

Cardinals vs. 49ers Predictions

• Pick #1: Under 47.5 (-105)
• Pick #2: Brock Purdy Over 16.5 Rushing Yards (-116)
• Pick #3: Trey McBride Anytime Touchdown (+175)

PICK #1: Under 47.5 (-105)

San Francisco has allowed 20 points in two games, seven against the Rams and 13 against Miami, third-fewest in the league. Arizona has scored 33, tied for 24th, and managed seven at home against Seattle in a game where Jacoby Brissett threw for 95 yards on 28 attempts. Both Cardinals games stayed under their closing totals, 47.5 at the Chargers and 40.5 against Seattle. Last season's two meetings split, one over and one under.

The price is fair rather than generous: 47.5 at -105 implies a 51.2% chance, and some books have 48 if you want the extra half point. Bettors lean the same way, with 56% of the money on 47% of the tickets. Weather won't be a factor. Saturday afternoon's National Weather Service forecast for Santa Clara has the morning clouds clearing by kickoff, 67 to 68 degrees, a northwest wind around 8 mph at kickoff that builds to 11 to 14 mph with gusts near 22 by the second half, and no rain.

What could push this over is San Francisco's own offense. The 49ers have scored 62 points, tied for fourth, and the 35 they hung on Miami sent that game over its 44.5 total. The defense that allowed those 20 points also had Bosa and Height, who played 68% and 54% of the snaps against Miami, and both are out. Arizona's secondary is without Johnson and may be without Max Melton (toe), who is questionable. The total has climbed a point since it opened, and the market's prices lean slightly to the Over once the vig is stripped out. The reason we still like the Under is what these teams have actually produced: three of the four games they have played stayed under 47.5 (34, 40 and 38 points), and the fourth, San Francisco's 35-13 win over Miami, cleared it by a half point. Arizona would need to look like a different offense for this to go over comfortably.

PICK #2: Brock Purdy Over 16.5 Rushing Yards (-116)

Purdy has run for 29 and 30 yards in his two starts. The line is 16.5.

He carried five times for 29 yards against the Rams in Melbourne while taking every offensive snap, then three times for 30 yards and a touchdown against Miami on 85% of the snaps. That cleared this number by 12.5 and 13.5 yards, and neither game asked much of him on the ground, since both were comfortable wins, 27-7 and 35-13. The pick doesn't hinge on Evans's hip either, which matters with inactives not due until about 90 minutes before kickoff: it doesn't require Evans to catch a pass, though a thinner receiving corps could change how often the 49ers throw and how often Purdy has to move. And 30 yards of quarterback rushing doesn't require a shootout, so this fits with the Under.

Eight carries in two games is not much to go on, and a quarterback's rushing total can turn on a scramble or two. The Miami game also showed how a lopsided score can shorten his afternoon, and San Francisco is favored by 8.5. At -116, the book is pricing this at 53.7%, so you are paying a little for the two-game trend.

There were other ways to play Arizona's quiet offense. Jeremiyah Love's Under 58.5 rushing and receiving yards (-116) and Marvin Harrison Jr.'s Under 33.5 receiving yards (-114) both held in both games, but each needs the same slow Arizona afternoon the Under already needs, so we left them off. Tyler Allgeier's Over 7.5 receiving yards (-109) cleared both games with 9 yards each time and is the alternative if you'd rather not touch a quarterback rushing prop.

PICK #3: Trey McBride Anytime Touchdown (+175)

Arizona has scored three touchdowns this season. McBride has two of them.

He caught 9 of 13 targets for 95 yards and a touchdown at the Chargers, then 8 of 10 for 41 yards and Arizona's only touchdown in the 31-7 loss to Seattle. The offense runs through him: 13 of Arizona's 37 targets in Week 1 and 10 of 26 in Week 2, on 80% and 88% of the snaps. Jeremiyah Love's rushing score at the Chargers is the only other Cardinals touchdown. Brissett (hip) practiced fully all week and carries no game designation, so the quarterback feeding McBride is set. LaFleur was asked this week about manufacturing touches for Marvin Harrison Jr., who has four targets in two games, and sounded skeptical. He pointed instead to McBride as "one of the best underneath guys in the world." San Francisco will also be without Bosa and Height up front.

Plus money on a player who gets more than a third of his team's targets is the appeal. At +175 the implied chance is 36.4%, and he has scored in two of two. FanDuel had +195 on Saturday evening if you shop around.

The obstacle is the same defense that makes the Under attractive: 20 points allowed in two games and 182.5 passing yards allowed per game, seventh-fewest, while Arizona has one touchdown since Week 1. Two games is a short streak. This pick does pull against the Under, but both can cash. A 24-13 final stays under 47.5 and leaves room for a McBride score. We took the touchdown over his Over 7.5 receptions (+113), which he cleared with 9 and 8 catches, as the higher-payout way to bet the same volume on a player with two of Arizona's three touchdowns. The receptions Over is the steadier alternative.

21+ (18+ where permitted). Odds subject to change. If you or someone you know has a gambling problem, call 1-800-GAMBLER.