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The wait is over. Week 1 of the regular season is ready to kick off, coming off Labor Day weekend, with all 32 teams' players going back to work. The business of winning games begins with 272 games in total before determining which 14 teams continue into the playoffs.
The early betting lines play into the unknown for the first set of 16 games, with so many coaching and personnel changes going into effect for real across the league.
The initial slate is tough to navigate with some tricky spreads, but there's no time to waste. Here's diving headfirst into another long season of fearless football forecasting:
(Odds courtesy of Caesars Sportsbook)
MORE: NFL Week 1 picks straight up
NFL picks against the spread for Week 1
Game of Midweek: Patriots at Seahawks (-3.5, 44.5 o/u)
Wednesday 8:20 p.m. ET, NBC and Peacock
The Patriots have had some offseason drama involving coach Mike Vrabel to add to their challenge of avoiding a Super Bowl hangover. New England wasn't close to beating Seattle in Super Bowl 60, losing 29-13. It's difficult to believe the Patriots can bridge the gap much in the immediate rematch, which is a true road game in front of a loud crowd while the Seahawks are being celebrated again. Although Seattle is battling some key injuries and free-agent losses, it still has the defense to frustrate Drake Maye again with Vrabel staying outcoached by Mike Macdonald.
Pick: Seahawks win 24-20 and cover the spread.
Game of Late Week: 49ers at Rams (3-5. 48.5 o/u) (in Melbourne, Australia)
Thursday 8:35 p.m. ET, Netflix
The Rams will debut their Aaron Donald-Myles Garrett defense Down Under, far from the Pacific Time Zone in when these rivals usually play. The 49ers' offense has been riddled by some injuries and has some offensive line concerns, which doesn't bode well for them keeping Donald and Garrett from putting pressure in Brock Purdy's face. The Rams' offense also faces a 49ers' defense in transition with Matthew Stafford having all the principal players back in a balanced, explosive attack.
Pick: Rams win 27-17 and cover the spread.
Game of the Week: Broncos at Chiefs (-2.5, 43 o/u)
Monday 8.15 p.m. ET, ESPN and ABc
The Chiefs are expected to rebound after a lost first playoff-less season in the era of Patrick Mahomes starting at QB, further marred by Mahomes suffering a torn ACL. Mahomes' speedy recovery and competitive fire will bring out his best early, but this time he can lean on former Seahawks Super Bowl MVP Kenneth Walker III and the running game to take pressure off him back in Eric Bieniemy's offense. The Broncos have a little more passing pop and hope to have more reliable running, but the Chiefs' reworked D helps win a battle of attrition.
Pick: Chiefs win 20-17 and cover the spread.
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Lock of the Week: Bears (-2.5, 47.5 o/u) over Panthers
Sunday 1 p.m. ET, Fox
On paper, this is a matchup between two NFC division winners from last season who both lost to the Rams in close playoff games. In reality, it's one ascending 11-6 Super Bowl contender (Chicago) being hosted by an 8-9 team (Carolina). Ben Johnson's offense will jump into overdrive out of the gate and around Bryce Young, the Panthers simply don't have the firepower to keep up with Caleb Williams.
Pick: Bears win 33-20 and cover the spread.
Upset of the Week: Giants (+2.5, 48.5 o/u) over Cowboys
Sunday 8:20 p.m. ET, NBC and Peacock
The John Harbaugh era begins in New York to turn the page, while Odell Beckham Jr. back playing for the Giants in prime time against the Cowboys is a welcome throwback. Jaxson Dart is set up for a nice Year 2 in the new offense of Matt Nagy. Between OBJ, a healthy Malik Nabers and new tight end Isiah Likely, Dart has plenty of weapons at home to match what Dak Prescott can do with CeeDee Lamb, George Pickens, and others. New York sets the tone for a promising first season under Harbaugh.
Pick: Giants win 27-24.
Buccaneers at Bengals (-3.5, 50.5 o/u)
Sunday 1 p.m. ET, Fox
Baker Mayfield might have only a few more seasons left as a Buccaneer and will get reacquainted all of the AFC North, including the Browns. Mayfield has lived up well to being a 2018 No. 1 pick with his fourth team, while 2020 No. 1 pick Joe Burrow is trying to stay healthy to produce more top-tier results with his first. Cincinnati is primed for a rebound season with its offense leading the way and Dexter Lawrence anchoring the defense, while the Bucs are closer to a big rebuild.
Pick: Bengals win 34-24 and cover the spread.
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Saints at Lions (-7, 49.5 o/u)
Sunday 1 p.m. ET, Fox
The Saints' offense will come in confident to start Kellen Moore's second season with Tyler Shough building on his rookie finishing momentum. Travis Etienne sparking the running game and being an outlet receiver will help plenty. The Lions' defense is a work in progress again around Aidan Hutchinson and Jared Goff is adjusting to a new offense. Detroit finds enough pop with Jahmyr Gibbs to win a dome team battle.
Pick: Lions win 24-20 but fail to cover the spread.
Jets at Titans (-2.5, 39.5 o/u)
Sunday 1 p.m. ET, CBS
The Jets used to be called the Titans, so opening with this game in Nashville makes sense; they'll also be facing their former coach, Robert Saleh. There's no doubt the Titans' transitional offense with Cam Ward under former Giants coach Brian Daboll has fewer questions than the Jets' version with former Colts coach Frank Reich. Tennessee's players will be more fired up to win this win for Saleh, as it also proves to be the more improved team from 2025.
Pick: Titans win 20-17 and cover the spread.
Ravens (-3.5, 47.5 o/u) at Colts
Sunday 1 p.m. ET, CBS
Lamar Jackson vs. Daniel Jones is a sneaky Week 1 affair as Baltimore's current NFL team takes on its previous one. Jackson and Derrick Henry will feel it early in Declan Doyle's offense, while the defense will also come flying again for Jesse Minter's defense. That sets up the Ravens to outproduce what the Colts get from Jones and Jonathan Taylor.
Pick: Ravens win 23-20 but fail to cover the spread.
Falcons at Steelers (-3, 42.5 o/u)
Sunday 1 p.m. ET, Fox
These teams met in Week 1 of 2024, with the Steelers winning 15-10 at Atlanta. This game could also be a defensive slog, with the Falcons not inspiring with their QB situation to support Bijan Robinson as much as needed. The Steelers have the debut of coach Mike McCarthy working with Aaron Rodgers again to ease the offensive change, with more pop in the passing game.
Pick: Steelers win 24-14 and cover the spread.
Browns at Jaguars (-7-5, 40.5 o/u)
Sunday 1 p.m. ET, CBS
The Browns' QB battle between Deshaun Watson and Shedeur Sanders flips to Watson battling his fellow former Clemson star QB Trevor Lawrence. Lawrence is loaded with weapons in Liam Coen's offense, even now minus Etienne. The Browns have shakier support around Watson and now a defense that will fall apart without Garrett.
Pick: Jaguars win 30-14 and cover the spread.
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Bills (-1.5, 44.5 o/u) at Texans
Sunday 1 p.m. ET, CBS
Josh Allen has seen Houston as a house of horrors in the past, now tied to the fact he's facing the NFL's toughest all-around defense right away. Allen, can however, grind this game out with a lot of him and James Cook on the ground, while the Bills' defense can cause some problems for C.J. Stroud's pocket passing. The Bills also figure to get a big play when needed from Allen's new go-to wide receiver, D.J. Moore.
Pick: Bills win 20-17 and cover the spread.
Dolphins at Raiders (-3.5, 40.5 o/u)
Sunday 4:25 p.m. ET, Fox
Fernando Mendoza won't get to guide the Raiders' much improved offense under coach Klint Kubiak at first, missing out on playing he NFL team from his hometown of Miami aftrer beating the Miami Hurricanes in his last college game. But the Raiders can get the job done with Kirk Cousins, their running game and a lot of tight end Brock Bowers. Malik Willis and De'Von Achane will come in ready to splash well together for the Dolphins, but their lack of receiving pop hurts early.
Pick: Raiders win 27-24 but fail to cover the spread.
Packers at Vikings (-1.5, 41.5 o/u)
Sunday 4:25 p.m. ET, CBS
The Packers have high hopes for Jordan Love, now with more expensive No. 1 receiver Christian Watson. But the running game is going through a shakeup with the off-field issues for Josh Jacobs and the defense won't have Jeff Hafley long-term or a healthy Micah Parsons short-term. The Vikings' D remains loaded for Brian Flores, while Kevin O'Connell will help call the right plays for Kyler Murray in the QB's winning debut.
Pick: Vikings win 23-20 and cover the spread.
Amber Searls, Brad Rempel-Imagn Images
Commanders at Eagles (-4.5, 46.5 o/u)
Sunday 4:25 p.m. ET, Fox
The Commanders have had too much offseason drama with Jayden Daniels than desired at the time their offense is changing under David Blough, including a new-look eceiving corps with Stefon Diggs and Chig Okonkwo. The Eagles have been rather solid in their transition minus A.J. Brown, ready for Jalen Hurts to deliver a new brand of balance and efficiency under Sean Manniion. Dan Quinn is hoping for bigger things from the Commanders' defense, but for now, Vic Fangio needs to worry much less for the Eagles.
Pick: Eagles win 27-20 and cover the spread.
Cardinals at Chargers (-10.5, 47.5 o/u)
Sunday 4:25 p.m. ET, CBS
The Chargers are breaking in Mike McDaniel to lead Jim Harbaugh's offense and also have Chris O'Leary jumping from college to replace Minter. The Chargers hope to becom a stronger running team and Justin Herbert to benefit well from that balance. But there will be some lumps early. The Cardinals' offense is dangerous passing under new coach Mike LaFleur and has rebooted well in the rushing attack with Tyler Allgeier and Jeremiyah Love. Arizona is being too undervalued in going from the desert to rather neutral L.A.
Pick: Chargers win 24-17 but fail to cover the spread.
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