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The Denver Broncos won two consecutive games before their Week 9 bye, so they’re both rested and among our best NFL upset picks for Week 10. We always look for the best NFL odds from our best sports betting apps when making our  NFL picks.

It’s been a disappointing stretch for the Buffalo Bills following a 3-0 run when they outscored their opponents 123-33 from Weeks 2 to 4. Buffalo dropped to 5-4 with last week's 24-18 road loss to the Cincinnati Bengals, and the Bills have seen significant movement in their NFL playoff odds because of their slump.

Despite Buffalo's struggles, the Bills are heavily favored to rebound strongly. But the Broncos, riding a wave of momentum with consecutive victories, including an upset against the Kansas City Chiefs, enter the game as a formidable opponent. The clash between the Bills and the Broncos promises an intriguing contest, with Buffalo seeking to assert dominance on their home turf and Denver looking to build on their recent successes, setting the stage for an engaging and closely watched game.

Check out our NFL Week 10 predictions and our Week 10 NFL props to accompany our best NFL upset picks for Week 10 (odds via our best NFL betting sites; pick confidence based on a 1-to-5-star scale).

NFL upset picks: Week 10

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NFL upset predictions

Cleveland Browns (+230 via FanDuel) vs. Baltimore Ravens ⭐⭐⭐⭐

Despite playing without Deshaun Watson for most of the season, the Cleveland Browns have managed to hang in the thick of the AFC North race, entering Week 10 two games back of the first-place Baltimore Ravens. Cleveland’s defense might be the best in the NFL right now, holding the Arizona Cardinals to just 58 total yards in last week’s 27-0 shutout win. Watson is showing signs of finally being healthy, throwing for 219 yards and two touchdowns without an interception in that game.

Lamar Jackson and the Ravens are on an even bigger roll, blasting the Seattle Seahawks 37-3 last week for their fifth win in six games. However, Baltimore has historically been prone to the occasional hiccup, losing at home in Week 3 to the Indianapolis Colts and dropping a 17-10 decision to the Pittsburgh Steelers two weeks later.

Baltimore hammered the Browns 28-3 when these teams met in early October, but Watson was scratched hours before the game, forcing Cleveland to give Dorian Thompson-Robinson his first career start at quarterback. Prior to that meeting, the Browns had covered in their previous two games against the Ravens and hadn’t lost by more than a touchdown in their previous five versus Baltimore.

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Jacksonville Jaguars (+140 via Caesars) vs. San Francisco 49ers ⭐⭐⭐⭐

How often do you find a road team favored over a team with a better record? That’s the case this week with the 6-2 Jacksonville Jaguars catching a field goal at some sportsbooks as they host the 5-3 San Francisco 49ers.

Not many would argue that the 49ers are the better of these two teams, but San Francisco certainly isn’t playing like it right now. The 49ers come out of their bye week having lost three straight after a 5-0 start, and San Fran was held to just 17 points in each of those three losses. They’re also 1-3 ATS on the road this season, including outright losses to the Cleveland Browns and Minnesota Vikings.

Any advantage San Francisco gets from a bye week is negated by the fact that the Jaguars are coming off one of their own. Before the week off, Jacksonville had not only rolled off five straight wins, it had done so during a grueling stretch that saw the Jags play two games overseas, return home for one game, and then play a road game four days later on Thursday Night Football. Four of those wins came by a touchdown or more.

The Jaguars have been a dangerous home underdog in recent years, winning six of their last seven outright in that situation. Jacksonville’s defense also matches up extremely well against San Fran’s power running game, holding opponents to less than 80 rushing yards per game on the season.

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Denver Broncos (+320 via FanDuel) vs. Buffalo Bills ⭐⭐⭐

Everyone wrote off the Denver Broncos after they were humiliated 70-20 by the Miami Dolphins in late September, but that may have been a mistake. Sean Payton’s crew has won three of five games since, thanks to a defense that is finally resembling last year’s elite unit. Over its past three games, Denver has allowed a grand total of 45 points — and two of those games were against the Kansas City Chiefs, whom Denver shocked 24-9 before enjoying a bye last week.

While Denver has exceeded recent expectations, the Buffalo Bills certainly have not. Sunday night’s 24-18 loss to the Cincinnati Bengals was Buffalo’s third defeat in its last five games, with the Bills’ only victories during that stretch coming by a combined 11 points against the lowly New York Giants and Tampa Bay Buccaneers. Josh Allen has already thrown nine interceptions this season, and the offense is averaging a paltry 20.2 points per game since early October.

Yes, it’s hard to imagine the Bills losing an important night game at home to Denver, but it was also hard to imagine Buffalo needing late defensive stands to avoid losing to the Giants and Bucs in other primetime home games over the past month. Given the opposing directions these two teams are headed, I’ll gladly take a shot with the rested Broncos at this fat price.

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NFL upset picks made 11/8/2023 at 2:25 p.m. ET.

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