NFL Week 6 is here, and this slate really has it all. The London series continues with an interesting matchup between the Denver Broncos and the New York Jets at 9:30 am ET on NFL Network, which will feed directly into a 1:00 pm ET window headlined by the Browns’ trip to Pittsburgh and the Seahawks’ cross-country trip to Jacksonville. In the afternoon window, newly-acquired QB Joe Flacco will face the Packers for the second time in less than a month, while Mac Jones and the 49ers head to Tampa Bay to play Baker Mayfield and the Buccaneers. All of that action leads into a heavyweight fight on Sunday Night Football between the Detroit Lions and the Kansas City Chiefs and a double-header on Monday night.
Here at Pickswise, we have you covered on EVERY GAME in Week 6. You can find our NFL picks on the side and total of each game, as our expert NFL handicappers carry an 88-69-1 overall record after Thursday’s result — good for +30.5 units! But for now, it’s time to break down our NFL best bets from our top handicappers.
NFL best bet: Browns +6 over Steelers (-110)
Odds courtesy of bet365 at the time of publishing.
Cleveland returns from London following a tough last-minute loss to Minnesota as the Browns head to Pittsburgh to face the rested Steelers. The Browns fell to 1-4 after a 21-17 defeat to the Vikings as 3.5-point underdogs. Minnesota scored with 25 seconds left as Cleveland was held to 17 points or fewer for the 5th time this season. QB Dillon Gabriel played well in his NFL debut, throwing 2 TDs, while RB Quinshon Judkins busted the 100-yard mark for the first time in his career with 110 rushing yards.
The issue is the fast turnaround from traveling overseas, taking on Pittsburgh, which was off after holding off Minnesota 2 weeks ago in Ireland. The Steelers improved to 3-1 with the 24-21 victory, as all 3 of Pittsburgh’s wins have come away from Acrisure Stadium. Steelers QB Aaron Rodgers has thrown 7 TDs and 1 interception in the 3 wins, while getting intercepted twice in the lone loss to Seattle. Cleveland’s pass defense ranks 4th in the NFL in yards allowed per game, but the Browns have intercepted only 2 passes this season.
Last season, these rivals split their 2 matchups with the home team capturing each game. Cleveland surprised Pittsburgh in a mid-November TNF thriller, 24-19, on a short Nick Chubb TD run in the final minute. In the 2nd meeting in the Steel City, Pittsburgh jumped out to a 27-7 lead and crushed Cleveland 27-14 as 6.5-point favorites. The Browns have not won at Pittsburgh since the 2020 season, dropping 3 of the last 4 meetings by double-digits. There will be a narrative that Cleveland has the quick turnaround from the London trip, as the public will likely be all over Pittsburgh in this spot. You can’t deny how strong Cleveland has been defensively, and Pittsburgh is 0-2 ATS as a favorite of at least 3 points this season. With this one expected to be a low-scoring battle, it’s worth grabbing the points with Cleveland to keep it close once again.
Read our full Browns vs Steelers prediction
NFL best bet: Patriots vs Saints Under 46 (-110)
Odds courtesy of Fanatics Sportsbook at the time of publishing.
Neither offense — especially that of New Orleans — inspires a ton of confidence. The Saints are #27 in scoring offense and #24 in total offense heading into Week 6. Rattler has not necessarily been bad, but he isn’t a playmaker under center and averages just 5.6 yards per pass attempt. If he isn’t going to get help from Kamara, the Saints will be in serious trouble. Kendre Miller will be the primary back on Sunday if Kamara can’t go; neither RB has done much of anything for New Orleans so far in 2025.
New England’s offense has been good enough to pick up 3 wins, but it’s hard to see success being sustained if it continues to be so one-dimensional. It is #27 league wide in rushing at 95.2 yards per contest on 3.7 yards per attempt. Here are the Patriots’ leading rushers in their 5 games: Henderson with 27 yards, Stevenson with 54 yards, Maye with 45 yards, Stevenson with 38 yards and Henderson with 24 yards. The Saints are stellar against the pass, ranking #7 in the NFL in that department and #3 in yards per pass attempt allowed (5.6). So this could be a favorable matchup for New Orleans’ defense if New England still can’t run the ball, as the home team should be able to keep Maye in check through the air. All things considered, 46 is too high of a number for these 2 teams.
Read our full Patriots vs Saints prediction
NFL best bet: Seahawks +1 over Jaguars (-115)
Odds courtesy of BetMGM at the time of publishing.
Two teams that have been rolling recently will meet here, as the Jacksonville Jaguars host the Seattle Seahawks in Week 6. Jacksonville has been one of the league’s most pleasant surprises at 4-1, while the Sam Darnold era in Seattle couldn’t have started much better — as the Seahawks enter this one having won 3 of 4 with the only loss coming in a game where they still scored 35 points. I’m a big Liam Coen fan, but I don’t think they’ve played as well as 4-1 might indicate, and I’m fading the Jags here.
Yes they picked up a thrilling 3-point comeback win over the Chiefs last week, but that took a herculean effort to squeak out, and the Seahawks are playing objectively better than the Chiefs right now. Jacksonville’s other 3 wins don’t look great when you look closely. First, they beat a terrible Panthers team, then a Texans team that was at rock bottom in an ugly 17-10 game, and then the 49ers in a game in which Brock Purdy returned too early from injury and played terribly. Now is the time to sell high on the Jags coming off their biggest win in quite some time because it’s not like Trevor Lawrence is actually playing well.
He’s averaging just 6.3 yards per attempt, by far the lowest mark since his rookie season, and has 6 touchdowns to go with 5 interceptions. It’s the complete opposite for Darnold, who has quietly been one of the most efficient quarterbacks in the league, averaging 9.3 yards per attempt. The Seahawks’ 2 losses this season came to good 49ers and Bucs teams, and they both were by 4 points or fewer. Jacksonville is also on a short week here off the draining victory as their win over Kansas City was Monday night, and everything is pointing toward Seattle here.
Read our full Seahawks vs Jaguars prediction
NFL best bet: Buccaneers -3 over 49ers (-105)
Odds courtesy of FanDuel Sportsbook at the time of publishing.
The Mac Jones era will continue on here for the San Francisco 49ers as they take on the Tampa Bay Buccaneers in Week 6. Jones has now gotten himself pretty banged up while filling in for an injured Brock Purdy, but he insists he’s going to be OK to play here. The 49ers better hope so, because the next man up is former UDFA Adrian Martinez, who has never thrown a regular season pass.
The prospect of a hobbled Jones going on the road against a very good (although quite injured themselves) Buccaneers team doesn’t sit right with me, so I’m going with Tampa. Even with all their injuries, the Bucs still just managed to beat a really solid Seahawks team on the road last week. And that was despite Sam Darnold lighting it up. Tampa isn’t getting enough respect for being 4-1 with their only loss on the year being in a close game to the defending champion Eagles. The 49ers are also 4-1, but their wins aren’t as impressive, and tellingly, all 4 of them have come by 5 points or fewer.
I’m not giving them too much credit for beating the Saints by 5 or the Cardinals by 1. San Francisco’s defense has looked really shaky, including in their one signature win of the season last week when they beat the Rams. Despite squeaking past Los Angeles in OT, they gave alarmingly gave up 389 yards and 3 touchdowns to Matthew Stafford. The week before that, they gave up 26 in an ugly home loss to Jacksonville. Christian McCaffrey is averaging an abysmal 3.1 yards per carry this year, and top 49ers wideouts Jauan Jennings and Ricky Pearsall are both dealing with injuries. Give me the Bucs minus the points.
Read our full 49ers vs Buccaneers prediction
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