Arizona Cardinals vs. San Francisco 49ers Odds, Spread, Preview: NFL Week 18 Predictions

By Lawrence Smelser

Arizona Cardinals vs. San Francisco 49ers Week 18 matchup preview and current betting lines

The 49ers will head to Glendale, AZ to take on the Cardinals Sunday. Kickoff is set for 3:25 p.m. ET and the matchup can be seen on FOX.

San Francisco (12-4) currently holds the No. 2 seed in the NFC and can leapfrog the top-seeded Eagles with a win over Arizona paired with a Philadelphia loss to New York. The Eagles will play at the same time.

Kyle Shanahan and his squad are arguably the hottest team in the NFL having won nine-straight contests. The organization is coming off a thrilling 37-34 overtime win over the Las Vegas Raiders.

Arizona (4-12) is one of the worst teams in the league and is currently on a six-game losing streak. Kliff Kingsbury and his men enter the game after a narrow 20-19 loss to Atlanta last Sunday.

The Cardinals have been inconsistent all year and things went from bad to worse when starting quarterback Kyler Murray tore his ACL midseason. Backup quarterback David Blough (0-1 this year) is scheduled to start under center.

FanDuel Sportsbook gives the 49ers a 14-point edge over the Cardinals. On the moneyline, Arizona is +640 and San Francisco sits at -950. 

The game total for the contest is set at 40.5 points. Bettors have placed 57% of their wagers on the Cardinals to cover the spread and 98% of the money is on the Niners to win outright. 

Players to watch in the Cardinals vs. 49ers contest


David Blough: The former Purdue Boilermaker will start his second-straight game for Arizona. Last week, Blough went 24-of-40 for 222 yards and a touchdown in the team’s 20-19 loss to Atlanta. 

San Francisco

Brandon Aiyuk: The former 25th-overall pick (2020) has been the offense’s WR1 this season. Aiyuk has amassed 74 receptions for 956 yards and eight touchdowns. Shanahan will likely have Purdy target Aiyuk often to give him the 44 yards he needs to reach the 1,000-yard mark for the first time in his career.

Cardinals vs. 49ers prediction and odds

Our NFL bet of the week for the Cardinals vs. 49ers

ESTNN is providing bettors with two free selections for this game.

Arizona vs. San Francisco Alternate Spread: 49ers (-9.5) @ -186 (FanDuel)

This matchup truly has a “David vs. Goliath” feel to it. The 49ers outmatch their opponents in nearly every statistical category.

Shanahan’s fifth-ranked offense is posting an average of 369.1 yards per game and 25.8 points per contest (seventh). They’ll line up against a Cards’ defense ranked fourth-worst in the league in points allowed (25.7). The unit is also surrendering 351.3 yards per contest (21st).

Kingsbury’s offense ranks both 21st in points per game (20.4) and yards per game (327.8). They’ll face a beast of a defense in San Francisco which ranks first in both points against (16.5 per game) and against the rush (78.8 per contest). The Niners also boast the No. 2 total defense allowing opponents to average just 303.4 yards per game.

After Jimmy Garoppolo went down for the season due to injury, Shanahan was forced to start his third-string quarterback, Brock Purdy. The last pick in the 2022 NFL Draft has likely played himself into next year’s role as QB1 due to a 5-0 record and his impressive resume.

Brock Purdy Stats

Passing yards: 1,196 

Touchdown passes: 10 

Interceptions: 4

Quarterback rating: 67.8 

Purdy’s QBR translates over a full season to fifth in the NFL.

The Niners will field a plethora of stars come Sunday including Pro Bowlers Christian McCaffrey, Deebo Samuel (set to return from injury) and George Kittle. Brandon Aiyuk has also played well this season and running back Elijah Mitchell is scheduled to be activated.

The last time these two teams met, San Francisco triumphed 38-10 in a romp. McCoy was the starting quarterback for Arizona that day. Cardinals’ star receiver DeAndre Hopkins has been ruled out for Week 18 which is a huge blow to their offense.

San Francisco is 10-6 against the spread this campaign and is 7-0 against NFC West opposition in its previous seven matchups. Arizona is 8-8 against the spread in 2022-2023 and is 1-7 ATS in its prior eight meetings against divisional opponents.

At ESTNN, we believe the 49ers will cover an alternate 9.5-point spread versus the Cardinals. FanDuel Sportsbook is offering -186 odds for the wager.

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Cardinals vs. 49ers odds: San Francisco team total over 27.5 points @ +100 (DraftKings)

Since Purdy took over as the starter in week 13, the Niner offense has been firing on all cylinders and is averaging 32.6 points per game (5.1 points more than the total offered at DraftKings). 

Throughout the five-game span, San Francisco has scored 33 or more points four times. The offense should have a great chance to do it again versus Arizona’s 29th-ranked scoring defense allowing 25.7 points per week.

Our pick is to take the over 27.5-point team total prop in favor of the 49ers on DraftKings at -100 odds. If you’re interested in learning about more prop bets for week 18, read our NFL player props page.

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Frequently asked questions regarding Arizona vs. San Francisco in Week 18

Purdy was drafted in the seventh round with the 262nd pick (last one). The last pick in each draft is nicknamed “Mr. Irrelevant”.

If you’re interested in seeing other game lines, read our NFL odds for this week page for more information. 

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