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Arizona Cardinals vs. San Francisco 49ers Week 5 Betting Preview, Odds, and Prediction

The Arizona Cardinals look to extend their undefeated run to five straight when they take on division rival San Francisco 49ers on Sunday. Can they come through as the bookies favorite?
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Arizona Cardinals vs. San Francisco 49ers Week 5 Betting Preview, Odds, and Prediction

Date: Sunday, October 10, 2021

Time: 4:25 PM ET

Location: State Farm Stadium, Glendale

Where To Watch: FOX

Arizona Cardinals Record: 4-0-0 SU, 3-1-0 ATS

San Francisco 49ers Record: 2-2-0 SU, 1-3-0 ATS

Click Here For Arizona Cardinals vs. San Francisco 49ers Betting Odds

Arizona Cardinals vs. San Francisco 49ers Preview

The Arizona Cardinals are the last undefeated team in the league after emerging with a perfect 4-0 record at the weekend following an upset over the Los Angeles Rams. The San Francisco 49ers have lost two on the trot, and they're in real danger of extending this negative slide with Jimmy Garoppolo questionable to start on Sunday. 

Lookahead lines had this game projected on a 2-point spread before Week 4, but after the weekend's action, books went to press with Arizona at -4. The root cause for this significant hike is twofold: a) Arizona's gauntlet-throwing win over the LA Rams to stay undefeated, and b) San Francisco's two-game losing streak marred by the injury to Garoppolo. 

On account of these developments, the balance naturally shifted towards the Cardinals. And since Sunday, the line's upward trajectory continued as the public bet up Arizona at home over San Francisco. As things currently stand, the Cardinals are laying 5.5 points to the Niners.

Arizona Cardinals Overview

Confidence in Arizona's value is clearly high, and it's partly underscored by Kyler Murray's outstanding play, which is earning him well-deserved, early MVP consideration. Murray ranks as the top bet to win the coveted award, and he sits on top of several NFL media QB Power Rankings this week.

Arizona didn't just beat the LA Rams; they routed Sean McVay's highly fancied Rams, 37-20, at SoFi Stadium. The outcome was worse than the deficit suggested, and it came nowhere near the projected betting odds, which closed with the hosts as the -3.5 point faves. 

Murray went 24-of-32 on his passes, threw for 268 yards, and had two touchdowns on the day. Running back Chase Edmonds had a banner day, running riot over the Rams defense as he put up 120 yards of the Cardinals' 218 rushing yards. James Connor added 50 yards and two scores on the ground. 

By the third quarter, the Rams defense looked gassed. Arizona's assault on the ground and in the air never let up. Veteran wide receiver AJ Green put up 67 yards and a touchdown on five receptions, and Maxx Williams added 66 yards and a touchdown on five receptions.

San Francisco Overview

San Francisco started the season by winning back-to-back games on the road, but it sputtered behind their first loss at home to the Green Bay Packers in Week 3. It was a heart-breaking loss, with the game snatched right out of their hands in the final 30 seconds of the game as Aaron Rodgers marched the Packers down the field to set up a game-winning field goal. 

The following week presented the Niners with a chance to rebound at home at the expense of the Seahawks. The game started positively, and the Niners took the lead early, but things went south quickly after Garoppolo exited the game at the start of the second half. Rookie Trey Lance took over from Garoppolo, and while he played well enough, the Niners succumbed to the 28-21 loss in the end. 

Arizona Cardinals vs. San Francisco 49ers Odds

49ers+195+5 (-108)Over 50 (-108)
Cardinals-200-5 (-110)Under 50 (-110)

Click Here For Arizona Cardinals vs. San Francisco 49ers Betting Odds

The market on this game isn't at all surprising. These two teams appear to be heading in opposite directions, and they currently bookend the NFC West standings. Add to that the uncertainty surrounding the Niners' starting position and other injury concerns facing Mike Shanahan, including Tight End George Kittle; it's no wonder the odds and the public are going against San Francisco.  

There is a small chance Garoppolo will play on Saturday, but he didn't practice on Wednesday due to his calf injury. The reports coming from San Francisco are that it's a game-time decision. If Jimmy G. is unable to play, it will mark Lance's first NFL start. Before the second half of last week's contest against the Seahawks, the total of Lance's NFL exposure amounted to seven NFL snaps. Before the 2021 NFL draft, Lance played only 17 games in college football. 

Arizona Cardinals vs. San Francisco 49ers Betting Preview

NFC West contests are typically fiercely competitive and utterly absorbing. For this clash to live up to the billing, though, Kyle Shanahan will have to have a full complement of starters at State Farm. Injuries turned San Francisco's season upside in 2020, and it's looking like it might do so again. 

So, this is one of those quintessential games that bettors must decide whether to bet now or later. The answer hangs on San Francisco's roster decisions and how bettors are slicing this game, whether they're backing Arizona to win and cover or the Niners to win, cover, or both. 

The fact is that if Garoppolo is ruled out, along with George Kittle (both currently listed questionable due to calf injuries), the point spread will likely go higher. Alternatively, if the pair get the nod, the point spread could shrink a fraction. 

For those on the fence here, the best betting strategy might be to wait it out to see what comes out of each camp and what number appears on the NFL odds board closer to game time.


Nikki Adams is a freelance sports writer that’s honed in on the world of sports betting. She joined OddsChecker in 2021 after having covered a number of major American sports, including NFL and NCAAF, for several other publications in the industry. When she’s not looking for the best betting angles and writing engaging and insightful articles, she’s likely on a tennis court or binging on reality TV.


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