NFL Thursday Night Football Best Bets: Lions vs. Bills Odds & Picks (Sept. 17)

Thursday Night Football brings one of NFL Week 2’s most intriguing point spreads and totals, with the betting market expecting plenty of offense when the Detroit Lions visit the Buffalo Bills. Buffalo is laying points at home, while an over/under north of 50 immediately puts both explosive offenses under the betting microscope.

(Photo by Bryan M. Bennett/Getty Images)

Both teams arrive 1-0, although their season openers unfolded differently. Buffalo erupted for 36 points in a 36-31 win over Houston, with Josh Allen throwing for 334 yards and accounting for four touchdowns. Detroit needed overtime to escape New Orleans, 31-30, after watching a 21-point advantage disappear.

That combination creates an intriguing handicapping question: How much should bettors react to one week of football?

There's also a historic backdrop. Buffalo will play the first regular-season game at the new Highmark Stadium, adding another layer to an already compelling prime-time matchup.

Before breaking down where the betting value may lie, here are the latest numbers for Thursday's game (odds via FanDuel):

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Detroit Lions at Buffalo Bills

• Spread: Detroit +5.5 (-115) | Buffalo -5.5 (-105)
• Moneyline: Detroit (+198) | Buffalo (-240)
• Total: O/U 54.5 (-114/-106)

The numbers provide the starting point, but finding value requires digging deeper into how these teams match up.

Detroit leaned heavily on Jahmyr Gibbs in Week 1, giving him 29 carries as part of a ball-control approach, while Buffalo displayed its ability to strike quickly behind Allen.

The short week adds another consideration, particularly for a Lions team coming off overtime and now traveling to Buffalo. Detroit must also determine how aggressively it can pressure Allen without exposing itself when he escapes the pocket.

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Thursday Night Football Best Bets: Detroit Lions vs. Buffalo Bills on Sept. 17 (FanDuel)

Matchups and situational edges become increasingly important when evaluating the side, total and player-prop markets. With that in mind, here are the best bets for tonight:

Over 54.5 Points (-114)

Buffalo provides the biggest analytical reason to expect another shootout. The Bills generated 409 yards and averaged 7.72 yards per play after attacking the Texans vertically. Allen attempted eight passes of at least 20 yards downfield, completing four for 155 yards and two touchdowns. That explosiveness creates the possibility of scoring drives that require very little clock.

Detroit offers a different route toward the same result. The Lions produced 369 yards and 31 points while running 73 offensive plays in their opener. Jared Goff attempted 39 passes without an interception; Detroit scored four offensive touchdowns and converted 80% of its red-zone opportunities. If Buffalo forces Detroit away from its preferred ball-control script, increased passing volume could accelerate the game considerably.

Trends Support Offenses

Betting trends reinforce the matchup. The Over is 6-2 in Buffalo's last eight games overall and 5-1 in its last six as a favorite. The Bills have also gone over in six of their last eight games against NFC opponents. In Buffalo's last 10 non-conference games, the final tally averages 56.2 points. Detroit, meanwhile, has gone Over in five of its last six Week 2 games. The Lions are on an 8-2-2 roll to the Over when facing AFC teams.

The key is Buffalo's ability to create explosive plays against a Detroit defense that just surrendered 30 points, paired with a Lions offense that can extend drives and finish them with touchdowns. Last season, 10 of Detroit's 17 games and nine of Buffalo's 17 finished Over the posted total. Something in the neighborhood of 31-27 or 34-24 gets this game across the number.

Lions +5.5 Points (-115)

Buffalo may have the quarterback advantage with Allen, but 5.5 points is substantial protection for a Detroit team that can control the clock and create pressure. The Lions' Week 1 numbers came while they had the ball for 36:51. That type of sustained offense can shorten Buffalo’s opportunities and keep Detroit inside the number.

Detroit's biggest matchup advantage may be its pass rush. The Lions recorded five sacks, nine quarterback hits and three takeaways against New Orleans. Aidan Hutchinson alone generated four quarterback hurries and two sacks, giving Detroit a legitimate way to disrupt an explosive Buffalo attack without needing to win a shootout possession-for-possession.

Buffalo also showed defensive vulnerability in its opener. Houston accumulated 381 yards, converted 43.8% of its third downs and scored touchdowns on 80% of its red-zone opportunities. Goff doesn't necessarily need explosive downfield plays if Detroit can consistently stay ahead of the chains and finish drives.

The Hook Matters

ATS history supports the pup here. The underdog has covered each of the last four meetings, while Detroit has historically performed particularly well when catching more than a field goal under Dan Campbell. The Lions are on a 20-7 ATS run as an underdog of more than +3 since he took over.

Yes, Detroit is coming off an overtime game on a short week and will be without starting offensive linemen Christian Mahogany and Blake Miller. That's especially relevant because Goff's effectiveness falls when pressured.

It's also why +5.5 is considerably attractive, especially against a Buffalo team that is 3-8 ATS when laying -3.5 or more since Sept. 18, 2025. The Bills are also mired in a 7-10 ATS skid when installed as a favorite against NFC teams since the 2022 season.

Amon-Ra St. Brown Anytime TD Scorer (+105)

Amon-Ra St. Brown opened the season by catching 10 of 14 targets for 67 yards and two touchdowns against New Orleans. Those 14 targets represented roughly a 36% target share, reinforcing that Goff continues to funnel the passing game through his most dependable receiver.

This isn't merely a one-game scoring spike. St. Brown scored 10 touchdowns in 2023, 12 in 2024 and 11 in 2025 - 33 receiving touchdowns across his previous 50 regular-season games. Add his two scores from Week 1 and he has reached the end zone 13 times over his last 18 regular-season games, including 2025 and this year's opener.

The last time St. Brown faced Buffalo, he caught 14 passes for 193 yards and a touchdown on 18 targets. In his two career meetings with the Bills, St. Brown has 23 catches for 315 receiving yards, has topped 100 yards both times and has two touchdowns.

W.G. Ramirez is a veteran sports writer from Las Vegas and a staff analyst at Ballislife Bets. Follow him on X at @WillieGRamirez.