Week 5 brought some unexpected outcomes, including the Tampa Bay Buccaneers defeating the Dallas Cowboys 24-16 on Thursday Night Football. The week also saw a 27-27 tie between the New York Giants and the Washington Commanders.
Which matchups stand out this week? Three particular clashes come to mind for this weekend.
Below, we’ll examine the schedule and discuss our best NFL Week 6 predictions, including picks for winners, spreads, over/under, team totals, and more on PrizePicks.
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Houston Texans vs. Jacksonville Jaguars Prediction on Spread for NFL Week 6
Time + How to Watch: 9:30 a.m. ET on NFL Network
The Jaguars remain in London for the second straight week. Last Sunday, a 57-yard field goal from K Cam Little propelled them to a 19-17 victory over the Eagles. Not only does Jacksonville sit atop the AFC South with a 4-1 record, but its +53 point differential is the second-best mark in the NFL.
The Texans are coming off a 26-3 win over the Titans but sit just 1-4 on the season. As they try to get back into the playoff picture, they made a splash this week by acquiring WR Marvin Harrison Jr. in a trade with the Cardinals.
Texans head coach DeMeco Ryans said that Harrison will play against the Jaguars. The former first-round pick disappointed with Arizona, recording 5 receptions for 85 yards and 1 TD over four games this year.
One of the reasons why the Texans have struggled is their inability to run the ball. They average 79.0 rushing yards per game, which is the second-lowest mark in the sport. Now, they'll be without RB David Montgomery (groin), who is considered week-to-week.
That means Houston will turn over the backfield to RB Woody Marks, who averages just 3.6 yards per carry for his career.
Things may not get any easier for the Texans on the ground with the Jaguars ranking third in the league in rush EPA/play allowed, per RBSDM. They're also seventh in dropback EPA/play, which has helped them allow only 14.0 points per game.
Jacksonville could ride its defense to a commanding victory.
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Buffalo Bills vs. Las Vegas Raiders Prediction on Spread for NFL Week 6
Time + How to Watch: 4:25 p.m. ET on CBS
In one of the most action-packed games of Week 5, the Bills defeated the Rams 37-34 in overtime on Thursday Night Football. QB Josh Allen dominated on the ground in the matchup, rushing 10 times for 121 yards and 1 TD.
Through five games, Allen has 7 passing TDs and 8 rushing TDs. The Bills have one of the best offenses in the league with Allen and RB James Cook III leading the way; their 32.8 PPG is tied with the Lions for the best mark in the NFL.
The Raiders’ offense has also been productive, averaging 26.4 PPG en route to a 3-2 record. The team was lit up by the Patriots last week, however, losing 45-17. It marked the first time this season Las Vegas had fewer than 26 points.
Even when the Bills dominate on offense, their porous defense often keeps their opponents in games. They sit 28th in dropback EPA/play and 23rd in rush EPA/play while giving up 28.2 PPG.
Of Buffalo's five games, three were decided by 5 or fewer points.
Since the start of the 2022 season, the Bills are a modest 19-18-1 against the spread on the road. With their defense struggling and the Raiders showing improvement with QB Kirk Cousins at the helm, this could be a close game that comes down to the final seconds.
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Arizona Cardinals vs. Los Angeles Rams Prediction on Over/Under for NFL Week 6
Time + How to Watch: 4:05 p.m. ET on FOX
The Cardinals’ defense is struggling again, allowing the most PPG (32.4) in the league. This isn't a new trend, considering they allowed 28.7 PPG in 2025. The main issue is the secondary, which has contributed to Arizona being 31st in dropback EPA/play allowed.
Arizona is tied with the Lions and Commanders for most passing TDs ceded (14) and has coughed up 18 completions of at least 20 yards.
The Cardinals' inability to defend the pass makes the Rams a nightmare matchup for them. WR Puka Nacua has dominated since his return from injury, recording 26 receptions for 263 yards over the last two games. He also had a receiving TD and a rushing TD during that stretch.
Rams QB Matthew Stafford has been great no matter who's been on the field at WR, posting three straight games with at least 317 passing yards.
The Cardinals couldn't stop Stafford in two meetings last season. In a 45-17 win by the Rams in Week 14, Stafford had 3 TDs. In a 37-20 triumph over Arizona in Week 18, he had 4 more passing TDs.
The Rams’ offense may handle the bulk of the work if the over hits. However, the Cardinals aren’t exactly a pushover. They throw a lot because of their defensive struggles, which has contributed to them averaging 21.6 PPG.
The loss of Harrison isn’t exactly significant given how poorly he was performing. Arizona still has TE Trey McBride and WR Michael Wilson to lead the way.
Arizona isn’t winning games with QB Jacoby Brissett, but he at least brings some life to the offense. He has 7 TDs over the last three games and has come away with at least 2 TDs in 13 of 17 games since taking over as the starter last season.
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The Jaguars could use their stifling defense against the Texans to earn another win in London. Elsewhere, the Raiders look to exploit the Bills’ underwhelming defense, and another high-scoring game could be on the table in the NFC West tilt between the Cardinals and Rams.
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