NFL Week 11: 49ers vs Cardinals Betting Preview & Predictions

The NFC West rivalry heats up as the San Francisco 49ers and Arizona Cardinals collide in Week 12. San Francisco welcomes back Brock Purdy, while Arizona continues to fight through injuries to key offensive playmakers. Books have priced the 49ers as if Purdy returns in peak form — but is the market overreacting?

Let’s break down the matchup, betting angles, and our best wagers for Sunday.

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49ers Enter Week 12 as Heavy Favorites — But Is the Line Inflated?

Brock Purdy returns to the lineup, and oddsmakers are treating the quarterback as if he never missed a snap. The 49ers have been dominant ATS this season, finally taking their first loss against the number last week. Still, the spread appears to be inflated considering San Francisco’s health concerns and Arizona’s ability to grind out competitive division games.

With Ricky Pearsall back in the mix and the 49ers’ offense returning to near full strength, conventional wisdom points to a San Francisco bounce-back. But the pricing may be too rich.

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Cardinals’ Offense: Injuries Leave Arizona One-Dimensional

Arizona’s offensive issues continue to pile up:

• Kyler Murray is out again

• Marvin Harrison Jr. is sidelined with appendicitis

• Bam Knight is banged up

• The passing game is reduced to Trey McBride or bust

With limited weapons and unpredictable quarterback play, Arizona will lean heavily on McBride and Michael Wilson in the passing attack. This is not an offense built to trade haymakers with San Francisco.

Expect a conservative, clock-churning approach reminiscent of their game plan against Dallas: slow tempo, win on first down, and keep Purdy off the field.

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First Meeting: A Blueprint for Another Low-Scoring Game

When these teams met earlier this season, the game was a dead under, landing in the mid-to-high teens (18–16). That matchup featured Kyler Murray — a far more dynamic threat than what Arizona brings into Week 12.

Given the Cardinals’ injuries, limited explosive playmakers, and their strong tendency to drag opponents into sloppy, low-possession games, another low total feels likely.

The Under 48.5 stands out as the best angle on the board.

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Can Arizona Cover Again? Divisional Matchup Trends Favor the Cardinals

Despite their offensive struggles, the Cardinals have a strange ability to play San Francisco tough. No matter how good or bad Arizona looks on paper, matchups between these teams often remain unexpectedly competitive.

With an inflated line and the 49ers still adjusting with Purdy back under center, the Cardinals catching points is worth consideration — even if it’s just a lean.

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Best Bets for 49ers vs Cardinals

1. Under 48.5 (Best Bet)

Injuries, tempo, and divisional familiarity all point to another low-scoring matchup.

2. Cardinals +Points (Lean)

San Francisco should win outright, but Arizona’s ability to muddy division games keeps them within range of a cover.

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San Francisco controls the game, Arizona shortens it, and scoring stays well below the posted total. Expect a grind-it-out NFC West battle.

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