49ers vs. Cardinals: NFL Week 5 betting odds, preview, and pick

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October 6th, 2021

The Arizona Cardinals will look to remain undefeated on the season when they host the San Francisco 49ers on Sunday in a key NFL West matchup.

Sun, October 10 2021, 8:25 PM

ARI Cardinals






O 49.5

SF 49ers






U 49.5

Is Trey Lance ready to assume the QB1 job?

San Francisco drafted their quarterback of the future this spring, but Trey Lance was sitting behind Jimmy Garoppolo to start the season. That changed in Week 4, when the rookie was forced into action after Garoppolo left with a calf injury in their 28-21 defeat to the Seahawks. Lance played well, completing half of his 18 pass attempts for 157 yards and two touchdowns as he used his legs to not only rush for 41 yards, but extended many plays in what looked like backyard football at times.

Garoppolo’s injury is just a bruised calf according to MRI results on Monday, and head coach Kyle Shanahan has said the veteran could be good to go on Sunday. He and left tackle Trent Williams are both key injury concerns, but many fans want Lance to get the start given what they saw from him against the Seahawks.

The 49ers will be going on the road to face a Cardinals defense that forced two turnovers against the high-flying Rams and asking the rookie to make his first start away from home might be a daunting task. Additionally, tight end George Kittle is dealing with a calf injury of his own, while kicker Robbie Gould will be out a month with an injury. No matter who starts at quarterback for San Francisco, they might be going in short-handed.

The 49ers will hope to recover from a defeat that saw them outgain Seattle by more than 200 yards of total offense, but a pair of turnovers and eight penalties were their undoing. Their defense held Russell Wilson under 130 yards passing on 16 completions, and that same blueprint will likely be employed against Kyler Murray to limit his scrambling ability.

Cardinals stunned everyone by dominating the Rams

Murray played well against the Rams, but he got plenty of help from Chase Edmonds. The running back toted the rock for 120 yards on just 12 carries, adding to Murray’s 268 yards through the air and a pair of touchdown passes. Arizona jumped out to a 24-13 lead and extended it to 34-13 in the third quarter as they cruised to the win, scoring on seven straight possessions at one point.

Arizona took sole possession of first place in the NFC West, but they know every division game will be a dog fight. Last season, these two teams split their series with the road team winning each time, and Arizona has lost three of the last four against the 49ers. However, they made a statement with how they dispatched Los Angeles, and they will need to do the same against a San Francisco defense that ranks 10th in passing yards allowed and 11th in yards allowed per play.

The defense was key to their win, as they recorded two early turnovers that led to a pair of touchdowns. However, they still yielded better than five yards per carry to the Rams, who were unable to run as much as they’d like due to falling behind. That must improve against San Francisco, especially if Lance is the starting quarterback, as it would likely mean a more run-oriented attack.

49ers vs. Cardinals Injury Report

San Francisco 49ersArizona Cardinals
PK Robbie Gould: IR (groin)
RB Eno Benjamin: Questionable (undisclosed)
OT Trent Williams: Questionable (shoulder)
OT Kelvin Beachum: Questionable (undisclosed)
George Kittle: Questionable (calf)
OT Justin Murray: Questionable (undisclosed)
Jimmy Garoppolo: Questionable (calf)
OT Joshua Miles: IR (ankle)

49ers and Cardinals Betting Trends

  • The 49ers are 4-9 ATS and 4-9 SU in their last 13 games
  • The Under is 4-1 in the 49ers’ last five games at Arizona
  • The Cardinals are 3-1 ATS this season
  • The Under is 4-2 in Arizona’s last six games
  • The Under is 6-3 in the last nine games between these two teams

The Cards will cruise to another victory

The lone unbeaten team remaining in the NFL, Arizona answered all doubts after its performance against the Jaguars with its dominance of the Rams. There is a possibility for a letdown in this game, especially since the Cardinals will have to split time preparing for two vastly different quarterbacks.

If San Francisco were at full strength, I would be hesitant to pick them to cover the spread. However, the loss of Gould is a big one, with the veteran headed to IR. The 49ers signed Joey Slye, who has made just 58 of his 73 career field goal attempts. In a close game, not having Gould will be a massive disadvantage for the visitors.

Arizona should cover the spread in this one, and with how their offense is clicking I expect them to perform better against the 49ers than they did last season when they scored just 36 combined points. Take the Arizona -5.5 spread, and then pair it with the team total Over for a nice Same Game Combo play as they top 30 points for the fifth time in five games.

Score prediction: Arizona 31, San Francisco 20

NFL Week 5 PICK: CARDINALS -5.5 (-110); SAME GAME COMBO ARIZONA -5.5 and Team Total O 27.5 (+143)

49ers vs. Cardinals pick powered by The Quant Edge

Our predictive engine is calling for a Cardinals clean sweep, with Arizona favored to win, cover the spread, and go Over 49.5 points.