The Cardinals will likely be without starting quarterback Kyler Murray, which means Colt McCoy will be under center. Arizona captured a win against a division rival with McCoy in the game last week, but that game came against the opponent's backup quarterback as well. Technically the 49ers are starting their backup quarterback, since Jimmy Garoppolo has taken over after Trey Lance's season-ending injury, but that's a much different situation than John Wolford playing in place of Matthew Stafford.
San Francisco has won two in a row since losing the first game of the Christian McCaffrey era, and has a chance to get on a roll. Will the Niners keep their streak going, or will the Cardinals pull off the upset? We'll find out soon enough. Before we break down the matchup, here's how you can watch the game.
How to watch
Date: Monday, Nov. 21 | Time: 8:15 p.m. ET
Location: Estadio Azteca (Mexico City, Mexico)
TV: ESPN | Stream: fuboTV (try for free)
Follow: CBS Sports App
Odds: 49ers -8, O/U 43 (courtesy of Caesars Sportsbook)
When the 49ers have the ball
A few weeks back, we wrote about the kinds of things we could expect the 49ers to do offensively with Christian McCaffrey in the fold:
Shanahan is one of the league's most inventive play-designers, and McCaffrey has a versatility unmatched by any nominal running back in the NFL. Since he entered the league in 2017, McCaffrey ranks 11th among running backs in snaps aligned as a perimeter wide receiver, and third in snaps lined up in the slot, according to Tru Media.
Combine his flexibility with that of Deebo Samuel, as well as Kyle Juszczyk and even Brandon Aiyuk, and we are going to see the Niners get into some wild stuff. Samuel, of course, is first among all wide receivers in snaps aligned in the backfield. He's been there on 15% of his snaps this season, which is about as often as he's lined up in the slot (19%). Juszczyk, who is a fullback and thus plays a far lighter snap load than most runners, still checks in sixth among backfield players in snaps out wide and second in slot snaps...
It's very easy to imagine the Niners dropping McCaffrey into a lot of the stuff they do in terms of moving players around to different positions and getting the ball in creative ways, largely because even the ridiculously bad Panthers offense found ways to do that every once in a while. Whether it was lining him up in the slot, sending him in orbit motion, or sending him out wide to get a smoke screen with blocking in front of him, we saw a bunch of stuff in Carolina that we are likely to see in San Francisco...
But the 49ers can get even more ambitious with McCaffrey because unlike, say, Jeff Wilson Jr. or Elijah Mitchell, or even Juszczyk, he is an elite, home-run threat as both a runner and a receiver. Inserting him in place of one of those three players can create even more space for guys like Samuel, and having Samuel aligned in the backfield or Juszczyk out wide or in the slot can create confusion for teams and thus more room to work for McCaffrey...
The passing game stuff San Francisco should be able to access with CMC on the field might be even more exciting. The concepts will remain the same, but who aligns where and how that threatens opposing defenses will be constantly changing. Imagine the Niners lining up in a spread look, shifting Samuel into the backfield, sending Juszczyk in motion and faking a hand-off to Samuel in that direction, then flipping a quick screen to McCaffrey the other way. Or Samuel in the backfield, Juszczyk out wide, CMC in the slot, and Aiyuk split out to the same side of the field.
And in the three games CMC has played with his new team, we've seen all of that and more. But in the most recent game, we also saw the Niners lean into having Elijah Mitchell spell McCaffrey for some of the lower-leverage running work, so they could maximize what they get out of their new star.
McCaffrey got all the third-down work and most of the goal line work, but ceded some early-down stuff and got almost none of the salt-the-game-away-with-the-team-up-multiple-scores-late work. And why should he? Mitchell is a good player anyway, and there's no real reason to risk McCaffrey's health in those situations. It helps that Mitchell ran so effectively, which he should be able to do in this contest as well, given his skill set and the relative weakness of Arizona's run defense compared to San Francisco's run blocking. Even if he doesn't get the 18 carries he did a week ago, he should get some work here.
San Francisco will surely use the threat of both McCaffrey and Mitchell to juice up the play-action passing game, and we'll see our fair share of screens to Samuel, Aiyuk, and Kittle to keep the Arizona pass rush off balance. Maybe things won't be particularly explosive unless somebody creates a ton of YAC, but they're highly likely to be efficient.
When the Cardinals have the ball
So, it sounds like Colt McCoy will be under center for Arizona, as Kyler Murray will apparently miss another game with his balky hamstring.
McCoy started last week against the Rams, completing 26 of 37 passes for 238 yards and a touchdown. In three games filling in for Murray last season, McCoy went 74 of 99 for 740 yards, three touchdowns, and a pick. That's actually pretty good! It's not exactly in line with McCoy's performance throughout the rest of his career (62.2% completion rate, 6.6 yards per attempt, 34 touchdowns against 29 interceptions, 8.3% sack rate), though, so we should perhaps not expect a repeat -- especially against a defense as good as San Francisco's. For a player who plays so infrequently and thus brings uncertainty, it's important to think about what we actually know will happen in this matchup.
So, what do we know? We know the Cardinals will spread the field. We know they'll try to get the ball to DeAndre Hopkins as often as possible. We know James Conner will get the significant majority of the snaps in the backfield. We know Rondale Moore will be the primary guy underneath, and that the absence of Zach Ertz will change things a bit on that front. (But we don't know what to expect from rookie Trey McBride.) And we know the Niners will likely generate a ton of pressure against an offensive line that seems likely to be overwhelmed.
None of that sounds like a recipe for offensive success. Perhaps McCoy defies expectations, but it's tough to envision the way it happens against this particular opponent.
Prediction: 49ers 24, Cardinals 10