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San Francisco 49ers vs. Arizona Cardinals Prediction and Preview

San Francisco 49ers vs. Arizona Cardinals Prediction and Preview

Undefeated Cardinals host the 49ers in critical NFC West matchup

The second half of the Week 5 NFC West doubleheader will take place on Sunday afternoon when the San Francisco 49ers take on the undefeated Arizona Cardinals in State Farm Stadium in Glendale. This is a critical game for both teams since the NFC West is living up to its billing as the best division in football so far in 2021.

San Francisco (2-2) is looking to get back on track after losing at home to fellow NFC West rival Seattle 28-21. The 49ers started off well on defense by not allowing a first down against the Seahawks on their first five possessions. Unfortunately, they were not able to keep that going, as Russell Wilson got things rolling just before halftime with a 12-yard touchdown pass to DK Metcalf to tie the game at seven. San Francisco had some defensive issues on a few drives in the second half as they were not able to keep Wilson from beating them with his legs. Rookie quarterback Trey Lance got his first bit of extended playing time after replacing Jimmy Garoppolo, who left the game with a calf injury. Lance went 9-of-18 for 157 yards with a touchdown and also picked up 41 yards on seven carries. He'll make his first start on Sunday and Lance's dual-threat abilities could give this offense a new dimension as he gains more experience.

Arizona (4-0) sent a resounding message to the rest of the NFL last Sunday to not underestimate the Cardinals as a contender in the NFC. The Cardinals dominated the Los Angeles Rams in a 37-20 victory at SoFi Stadium. Kyler Murray went 24-of-32 for 268 yards, two touchdowns, and, most importantly, zero interceptions. It was a big step forward for Murray as the game seems to be slowing down for him in his third season. Chase Edmonds rushed for 120 yards on 12 carries, including a 54-yard run. A.J. Green, DeAndre Hopkins, and Maxx Williams led a balanced attack through the air, combining for 14 receptions, 200 yards and two touchdowns. The defense did a good job of playing a bend-but-don’t-break style, allowing 401 total yards. However, the Cardinals stepped up and forced two turnovers, an interception by Byron Murphy Jr. and a fumble recovery by Budda Baker. The red zone defense was solid too — the Rams scored just twice on four opportunities inside Arizona's 20-yard line.

San Francisco (2-2) at Arizona (4-0)

Kickoff: Sunday, Oct. 10 at 4:25 p.m. ET
TV: FOX
Spread: Cardinals -5.5

Three Things to Watch

1. Can the Arizona offense keep on rolling?
Murray is off to a great start this season, completing 76.1 percent of his passes for nine touchdowns and four interceptions. This start has made him the odds on favorite to win the MVP at +450, according to DraftKings Sportsbook, which puts him ahead of Kansas City quarterback Patrick Mahomes (+650).

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The Cardinals also have gotten plenty of production from their running game with Chase Edmonds and James Conner carrying the load instead of Murray. Arizona is sixth in the league in rushing, with the two running backs accounting for 77 percent of the carries. Murray does have three rushing touchdowns, but he's only totaled 23 attempts in the first four games. He averaged more than six per game last season.

Depth at wide receiver also has been a factor early on, as four different players already have 200 receiving yards. Pass protection has some room to get even better, though, since Murray has been sacked eight times. This week will provide a stiff test for the offensive line because the 49ers have had success in this respect. Last season, San Francisco recorded five sacks and pair of interceptions in the two meetings with Arizona, which were split with the road team winning each time. On Sunday, the Cardinals will likely stick to the script that has worked so well for them, especially taking some shots downfield against a banged-up, vulnerable 49ers secondary.

2. 49ers' quarterback situation
The media will keep hammering this storyline until someone can pull away and lock down the starting quarterback job. Garoppolo didn't practice all week because of the calf injury and was ruled out on Friday afternoon, meaning Lance will make his first career start. When healthy, Garoppolo is a quality starting quarterback who can win plenty of games. But the problem has been his ability to stay on the field. 

Lance is the more mobile, athletic signal-caller, and with the aggressiveness of Arizona's defensive front, you wonder what sort of game plan head coach Kyle Shanahan will put together for the rookie. The potential ceiling for Lance is high, but you want to make sure you put him in the best position to succeed and not ask him to do too much. There's a reason that Lance only saw limited playing time prior to Garoppolo getting hurt. This storyline will be fascinating to watch, especially if Lance leads his team to a win on Sunday.

3. Arizona’s ability to handle having a target on its back
If the Cardinals want to make the playoffs under head coach Kliff Kingsbury, they will need to keep playing consistent football. Last year, Arizona was 6-3 and lost a tough 28-21 battle at Seattle on a Thursday night. That loss sent the Cardinals in the wrong direction, as they lost five of their last seven games to miss the postseason. 

This team has a different feel after the front office bolstered the depth of the roster in the offseason by signing established veterans like Conner, Green, and J.J. Watt. All three are not only talented players at their respective positions, but also quality, high-character guys who know what it takes to win consistently in the NFL. Bottom line, if the Cardinals can keep the foot on the gas pedal, stay healthy, and protect their home field, then a playoff run could be in play this season.

Final Analysis

These two teams should put together another tough, rugged hard-fought battle for 60 minutes (if not longer). Special teams have the potential to be a difference-maker since Arizona is in better shape health-wise with the combination of kicker Matt Prater and punter Andy Lee, who can flip field position with his foot. San Francisco put kicker Robbie Gould on IR this week after he injured himself last week during pregame warmups. So they are turning to journeyman kicker Joey Slye. Overall, the Cardinals will pull away late to improve to 5-0 heading into a tough road game at Cleveland. As for the 49ers, it will be another tough loss but a great learning experience for Lance as he will do enough to keep the quarterback controversy going for the foreseeable future.

Prediction: Cardinals 33, 49ers 24