The NFL has a funny way of making experts look like amateurs by the time October rolls around. If you’ve been following the 2025 season, you know exactly what I’m talking about. Week 5 was a total meat grinder that left the "safe" picks in the trash. Now we’re staring down a Week 6 slate that feels like a trap waiting to spring.
Picking games straight up isn't just about looking at a win-loss column. Honestly, it's about vibes, injuries, and realizing that a "bad" team is often just one healthy left tackle away from an upset.
The Prime Time Heavyweights
Let’s talk about the Detroit Lions traveling to Arrowhead. Most people see the Chiefs at home and automatically click that moneyline. Big mistake? Maybe. The Lions are sitting at 4-1 and finally playing like the juggernaut Dan Campbell promised. They’ve been averaging over 40 points in their last few wins. Meanwhile, Patrick Mahomes and the Chiefs looked human—kinda shaky, actually—in that mistake-filled loss to the Jaguars. If Detroit’s defensive line can pressure Mahomes without blitzing, they’re taking this one. I’m leaning Lions in a "passing of the torch" type of regular-season moment.
Then you have the Monday night doubleheader.
The Buffalo Bills are heading to Atlanta. Josh Allen is coming off a messy game against the Patriots where turnovers basically handed New England the win. Atlanta is 2-2 and inconsistent, but playing at Mercedes-Benz Stadium is never a walk in the park for visitors. Still, expect a Buffalo bounce-back. They don't usually let two bad games spiral.
On the other side of Monday night, we’ve got the Bears at the Commanders. Jayden Daniels is back under center for Washington, and that changes everything. Chicago’s defense is solid, but they struggle with mobile quarterbacks who can extend plays for six or seven seconds.
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NFL Week 6 Picks Straight Up: The London Factor and Home Dogs
The Broncos and Jets are crossing the pond to play at Tottenham Hotspur Stadium. It's a 9:30 a.m. ET kickoff, which means half the players are still waking up when the ball is kicked. Denver is riding high after a massive statement win over the Eagles. Bo Nix is starting to look like he actually belongs in the league, and Sean Payton’s confidence is clearly rubbing off on the kid. The Jets? They’re a mess. Their scoring defense is near the bottom of the league and they haven't been taking the ball away. Denver wins this one on the ground.
- Tampa Bay Buccaneers vs. San Francisco 49ers: This is the game of the week that nobody is talking about enough. The Bucs are 4-1, but they are playing with fire. All four of their wins were decided in the final minute. Is it magic or just luck? They just lost rookie sensation Emeka Egbuka to a hamstring injury, which hurts. But the Niners are reeling too—Fred Warner is out for the season with that ankle dislocation. That’s the heart of their defense gone. Give me Baker Mayfield to find a way, yet again.
- Green Bay Packers vs. Cincinnati Bengals: Don't let the Bengals' record fool you. They’re starting Joe Flacco while Joe Burrow works his way back for December. The Packers are massive favorites at Lambeau (roughly -14.5), and for good reason. Jordan Love is healthy, and Cincy’s defense gave up 21 points in a single quarter last week.
- Pittsburgh Steelers vs. Cleveland Browns: A classic AFC North slugfest. The Steelers are 3-1, but it’s been ugly. Aaron Rodgers is leading the charge in Pittsburgh now, and while it isn't always pretty, he manages the game better than whatever is happening in Cleveland. The Browns' injury report is a novel at this point—David Njoku and Jack Conklin are both banged up. Steelers win a low-scoring, boring game.
Why the "Sure Things" Usually Fail
You’ve got the Philadelphia Eagles playing the Giants. On paper? Eagles all day. But look closer. The Eagles’ offense has been weirdly stagnant. They’ve basically stopped running Saquon Barkley in the second half of games, which is baffling. If they don't fix that coordinator-player disconnect, the Giants (who just embarrassed the Eagles recently) could pull off a shocker at MetLife. I’m sticking with Philly, but my hand is shaking while I type it.
Baltimore is in a world of hurt too. Lamar Jackson is out with a hamstring issue, and Roquan Smith is sidelined as well. They’re facing a Los Angeles Rams team that has Matthew Stafford playing like he’s 25 again. Without Lamar, the Ravens' offense loses its soul. The Rams should cruise here, especially with the Ravens' defense missing its best playmaker in the middle.
Navigating the Mid-Tier Muddle
There are a few games this week that are basically a coin flip.
The Jaguars are hosting the Seahawks. Jacksonville is finally "for real" after beating the 49ers and Chiefs back-to-back. Trevor Lawrence looks decisive. Seattle, however, has some major issues on the offensive line with Josh Jones out. If the Jags' pass rush gets home, it's a long day for Geno Smith.
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Dallas at Carolina is another one. The Cowboys demolished the Jets last week, and Dak Prescott is finally in a rhythm. Carolina is 2-3 and playing better under Kellen Moore, but they don't have the horses to keep up with CeeDee Lamb and the Dallas track meet.
Strategy for Straight Up Picks
- Check the Friday Injury Report: This is where the real info lives. If a starting center is "Doubtful," the whole game plan changes.
- Fade the Travel: West Coast teams traveling east for early games (1:00 p.m. ET) historically underperform.
- Look at Red Zone Efficiency: Teams that kick field goals instead of scoring touchdowns lose to teams like the Lions and Chiefs. Every single time.
The reality of NFL week 6 picks straight up is that momentum is a myth, but health is everything. Keep an eye on the Baltimore injury situation specifically; if Lamar Jackson is a surprise active, that game flips on its head. Otherwise, trust the teams with the stable quarterback situations and the better offensive lines.
Go through your list and highlight the "must-wins." For teams like the Bengals and Dolphins, they are basically playing for their season this week. Desperation is a powerful motivator in the NFL, often more so than talent alone. Focus on the turnover margin as your tie-breaker. The Jets haven't forced a turnover in weeks—that’s a massive red flag.
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Get your picks in early but keep a window open for those final inactive reports 90 minutes before kickoff. That is usually where the money is made or lost. In a week full of international travel and backup quarterbacks, the most prepared team usually survives, even if they don't thrive. It’s going to be a wild Sunday. Stay sharp.
Actionable Next Steps:
- Monitor the Baltimore Hamstrings: Check the final status of Lamar Jackson and Roquan Smith on Sunday morning; if both are out, the Rams' moneyline is the strongest play of the day.
- Track the London Weather: While the game is in a stadium with a retractable roof, the travel fatigue for the Jets' aging roster compared to the younger Broncos' core is a significant edge for Denver.
- Watch the Line Movement: If the Eagles' line drops below -6, it suggests sharp money is worried about the Patullo-Hurts chemistry issues.