49ers vs Cardinals Monday Night Football Picks and Predictions: Niners Dominate the Full 60

Monday Night Football goes south of the border for an international showcase in Week 11. The San Francisco 49ers and Arizona Cardinals clash inside Estadio Azteca in Mexico City.

NFL odds have a beefy spread set for this neutral site contest, padding that line due to the uncertainty in the Arizona passing game. Quarterback Kyler Murray is questionable with a hamstring injury, as is top target DeAndre Hopkins, leaving backup Colt McCoy as the potential passer in an offense that will also be without TE Zach Ertz. 

On the other hand, San Francisco is about as healthy as it’s been all season, which is saying something. The Niners enjoyed a bye two weeks ago and are coming off a pair of wins over the Los Angeles teams. San Francisco was actually swept in both matchup with Arizona last season and has lost three of its last four in this NFC West rivalry.

I break down the point spread and Over/Under total for Monday Night Football and give my best NFL betting picks and predictions for 49ers vs. Cardinals below.

Want more MNF plays? Check out our favorite player prop picks for the game, as well as our Jimmy Garoppolo spotlight player prop picks.

49ers vs Cardinals best odds

49ers vs Cardinals picks and predictions

It’s a weird spread for a weird game, honestly.

Books are padding against the potential injury issues for this Cardinals passing game, with Murray and Hopkins both questionable with hamstring ailments and backup Colt McCoy, not as much of a downgrade as some would think.

Oh, yeah. You might have heard: this game is being played in Mexico City. 

That does work against Arizona, not only from a personnel and matchup standpoint with a grinder of a Niners team, but also from a situational handicapping angle as well. The Cards were forced to give up a home game for this international showcase, which means another week of travel — with the added logistical hoops for getting everyone and everything over the border. 

Arizona will be playing its second travel game in a row and its third game away from home in four weeks — a tough schedule spot for any club. The Cardinals don’t have a bye until Week 13 while San Francisco enjoyed a bye two weeks ago and enters this game in relatively good health, for its standards.

The cherry on top of this NFC West war is that it’s being played 7,200 feet above sea level in Mexico City, which means conditioning and recovery will be tested in the energy-sapping thin air of Estadio Azteca. Sprinkle in the smog and local pollution from the fifth-most densely populated city on the planet, and who knows how teams will react. 

Niners head coach Kyle Shanahan opted to practice at altitude this week, taking the team to Colorado Springs (which is still only 5,600 feet above sea level) while Cardinals coach Kliff Kingsbury opted to stay put, do in-house altitude conditioning and stick to the routine before traveling to Mexico on Saturday.

Taking the spread, injuries, and situational factors out of the mix for a second, we know San Francisco is the better team on both sides of the ball. Shanahan’s playbook is a plodding, relentless rollout of elite playmakers and he’s going to give touches to whoever's feeling frisky that day. 

Defensively, you have one of the best stop units in the NFL potentially going up against a backup QB without his top target and minus his safety blanket in injured TE Zach Ertz. The 49ers are an elite pass rush that causes chaos without needing extra bodies and has limited seven of its nine opponents to 19 points or less.

All that said, we’re going to opt for a simpler approach: passing on the points and playing San Francisco on the double result, also known as the first half/full game odds.

Given the current spread, the 49ers are as expensive as -400 to win outright (and could be close to -500 if Arizona’s injured stars sit) but only -150 to win the first half and win the game.

San Francisco enters Week 11 as the No. 9 1H offense in DVOA at Football Outsiders, averaging 12.4 points in the opening 30 minutes. On the flip of that metric, the 49ers are the No. 4 1H defense in DVOA and check foes to only 8.6 points against in the opening two frames.

From there, the depth of the Niners’ offense will take over in the second half as the altitude in Mexico City starts to impact both teams. If Shanahan’s “That’s what science says” approach to altitude holds up, he has the horses to wear down an Arizona defense that has budged for big points in recent weeks, including 75 total second-half points in the past four games.

Going with the double result on San Fran trims the cost of the full-game moneyline with moderate risk (49ers are -4.5 1H Faves) while protecting against Arizona’s last-minute injury updates (positive or negative). It dances around an already big spread that could get bigger while leveraging a situational spot and matchup that favors the 49ers.  

My best bet: 49ers double result (-150 at bet365)

49ers vs Cardinals spread analysis

The look-ahead line for this game in Mexico City was San Francisco -1.5 before the start of the season. That spread was sitting at -5.5 before the events of Week 10. And with the Niners edging the Chargers and the Cardinals beating a depleted L.A. Rams team with backup Colt McCoy, this Week 11 neutral site spread re-opened at 49ers -6.

However, with the status of Murray and Hopkins in question, and San Francisco garnering weekly money from the betting markets, this spread spiked and blew through the key number of a touchdown and sits as high as -8.5 at some respected online shops. 

The 49ers not only have a loaded offense that ranks 11th in EPA per play, but the defense is getting healthier and is really the backbone of this squad. 

The Niners are No. 5 in EPA allowed per play, anchored in a pass rush that ranks fifth in pressure rate per dropback and has stacked 29 QB sacks on the year. San Francisco can get this pressure without blitzing much, generating quality rushes with the front four and allowing linebackers to drop back in coverage or closely spy the quarterback.

McCoy has proven himself a worthy backup and Arizona’s offense may not take the same tumble other attacks do when turning to the second stinger. He was a solid 26-for-37 passing with 238 yards vs. the Rams last week, with 98 of those gains coming from Hopkins. If both Murray and Hopkins miss the Monday nighter, the Cardinals will climb to double-digit dogs.

49ers vs Cardinals Over/Under analysis

This total opened at 44 points on Sunday night and has moved down slightly to 43.5.

The Niners' offense while very efficient with multiple options, is methodical in its pace, and runs a play every 29.79 seconds — fifth slowest in the NFL. San Francisco sits 22nd in plays per game and its relentless attack could wear down the Cardinals' defense quickly, given the game is being played 7,200 feet above sea level in the extremely thin air of Mexico City.

Arizona is a quicker offense, averaging the most plays per game in the league entering Week 11. The Cardinals call an offensive play every 26.44 seconds — fourth fastest. The offense has seen improvements since the return of Hopkins from suspension in Week 7, ranked 16th in EPA per play after sitting 20th in the opening six weeks of action.

As for the Cardinals' defense, it is an aggressive approach that brings the blitz on 37.5% of dropbacks — third most in the NFL. Arizona has cooked up a pressure rate of 24.4% but has only 19 sacks on the season — despite throwing the kitchen sink at QBs.

The Cardinals enter Week 11 with a 5-5 Over/Under count on the season, having played Over in four straight outings. The 49ers lean toward the Under with a 3-6 O/U record but is 2-1 O/U in the past three games.

49ers vs Cardinals betting trend to know

Since Kyle Shanahan took over as head coach in 2017, the 49ers are 7-11-1 ATS when laying more than six points, including 1-4-1 ATS as a favorite of -6.5 or higher vs. a divisional opponent. Find more NFL betting trends for 49ers vs. Cardinals.

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