NFL Week 5 Upset Predictions & Picks | Biggest Upsets for Week 5

Last Updated: Oct 8, 2021

Week 5 of the NFL season is upon us, and the overreactions are loud on the streets. We’re only a quarter of the way through the regular season, so we only have some idea about which teams are contenders and which are pretenders.

That said, the small sample of games that have been played can be dug through and sprinkled with context to become useful. Team-adjusted stats like DVOA have some value, and we also have to be cognizant of how injuries have affected teams in the early going.

Also, it’s not a huge shock when rookies or new teammates aren’t clicking immediately. As the season goes on, we should expect more cohesion.

With that in mind, let’s dive into some NFL Week 5 upset predictions and best bets. All NFL gameday odds are current as of 9 AM EST on Friday, October 8.

NFL Week 5 Upset Predictions

San Francisco 49ers vs Arizona Cardinals

The Arizona Cardinals are rightful favorites here given that they are undefeated and coming off a massive win against the Los Angeles Rams. Meanwhile, the 49ers are 2-2 and possibly starting their rookie QB for the first time this season. While Trey Lance may be raw, last week he flashed the arm talent and athleticism that made him a top-3 overall draft pick.

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Were Jimmy Garoppolo (calf) healthy we wouldn’t be discussing this game right now, but Lance adds that extra dimension to the offense necessary to beat Arizona. Division matchups are always wonky and the lack of tape on Lance in San Francisco’s offense can work to Kyle Shanahan‘s favor in catching the Cardinals’ defense off-guard.

Arizona ranks much worse against the run than the pass and even with a strong front seven, they will struggle to read Lance, Deebo Samuel, and rising rookie RBs Trey Sermon and Elijah Mitchell (if active).

Upset Prediction: 49ers 30, Cardinals 27

49ers vs Cardinals Upset Picks

Upset Pick: 49ers Moneyline (+190) at BetMGM

The 49ers are capable of eeking out a win in what figures to be a high-scoring affair. The Cardinals may be without Chase Edmonds, which would significantly disrupt their rushing attack given James Conner‘s struggles thus far and make their offense easier to defend against.

San Francisco’s star LT Trent Williams (shoulder) looks on track to play this week, which could give a huge boost to the 49ers’ run game and provide Lance more protection. His presence should help the 49ers exploit the Cardinals’ vulnerable run defense.

This bet somewhat hinges on whether George Kittle (calf) is active for San Francisco, but he seems likely to suit up after playing last week without re-aggravating his injury.

Upset Pick: Over 50 (-110) at BetMGM

San Francisco’s defense is overrated and Arizona’s defense is susceptible to the run. This game won’t be a traditional shootout, but plenty of points will be scored at the hands of two of the NFL’s most athletic QBs.

Trey Lance San Francisco 49ers QB

Trey Lance’s rushing ability could be instrumental in helping the San Francisco 49ers upset the Arizona Cardinals in Week 5. (Image: USA TODAY Sports)

Buffalo Bills vs Kansas City Chiefs

This may sound crazy, but the Buffalo Bills are the best team in football right now. As great as their offense has been, their defense has been even better, ranking first in overall DVOA and when adjusted for variation. This team is legit on all fronts, with their only weakness being the offensive line.

The beauty of this matchup for them is that the Chiefs’ biggest weakness is their front seven. While Chris Jones is a premier DT, the other pieces around him are so bad that Jones is forced out of position to edge rusher, further limiting him.

Buffalo also finally found its groove on the ground as both Devin Singletary and Zack Moss are enjoying hot starts to the season. This added strength will punish Kansas City’s defense and take some pressure off Josh Allen.

Upset Prediction: Bills 27, Chiefs 24

Bills vs Chiefs Upset Picks

Upset Pick: Under 56.5 (-110) at BetMGM

Both teams have the firepower to put up tons of points with Allen and Patrick Mahomes, but Buffalo’s defense should be able to slow down Mahomes. If not, the Bills are capable of taking an early lead against the Chiefs’ suspect defense and bleeding clock in the second half with their newfound run game.

Upset Pick: Bills Moneyline (+120) at BetMGM

Buffalo should take this one because they are the better team right now. Even though Kansas City has home-field advantage, that isn’t enough to make up the difference between these two teams, making the Bills moneyline our NFL pick of the day.

Cleveland Browns vs Los Angeles Chargers

The Cleveland Browns and Los Angeles Chargers both look like AFC powerhouses this season, so this should be an exciting game. It also creates the possibility of an upset, as both teams have legitimate chances of winning.

Cleveland is running a supercharged version of last year’s team with a top-10 defense (first against the rush) and an offense that has Odell Beckham Jr. back in action. The offensive line is playing great as usual, making this a tough offense to defend against as they can beat teams on the ground or through the air.

The Chargers, on the other hand, are more pass-heavy with Justin Herbert under center. While Austin Ekeler is one of the league’s best running backs when healthy, he does much of his damage in the receiving game. That should enable Cleveland’s secondary to sit back in coverage and force Herbert into tight windows, limiting his effectiveness and allowing the Browns to grind out a victory.

Upset Prediction: Browns 21, Chargers 17

Browns vs Chargers Upset Picks

Upset Pick: Under 46.5 (-105) at BetMGM

As expected, Cleveland’s defense is playing at an elite level. They have playmakers at every level of the defense and are healthy. Los Angeles should be able to move the chains against them, but chunk plays will be tough to come by given their lack of speed on offense. Cleveland can easily gouge the clock with their run game as well.

Upset Pick: Browns Moneyline (+110) at BetMGM

The Browns match up well against the Chargers. Their strengths are LA’s weakness and their faults aren’t going to be easy for LA to leverage in their favor. As long as the Browns aren’t forced to rely on Baker Mayfield too much, Cleveland should prevail here.

Thanks for reading our NFL Week 5 Upset Predictions! For more NFL betting tips, check out our NFL Week 5 Best Bets and NFL Week 5 Prop Bets.


Kev Mahserejian

Kev Mahserejian is an NFL/NBA/MLB analyst at The Game Day, residing in Los Angeles, CA. He graduated from the University of Southern California in 2017 and began creating sports content soon after. Kev currently writes fantasy and betting pieces while also hosting his podcast The Operating Room with various guests from the sports industry to discuss topics primarily regarding fantasy. He also writes for RotoBaller and is quite active on his Twitter @RotoSurgeon.

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