Detroit Lions vs. Buffalo Bills Prediction, Odds and Pick: Back Buffalo in Highmark Stadium Opener

Josh Allen faces a depleted Detroit secondary on Thursday Night Football, while injuries along the Lions’ offensive line strengthen the case for Buffalo.

Buffalo gets the celebration. Detroit gets the difficult assignment.

The Bills open the regular-season schedule at their new Highmark Stadium on Thursday, September 17, hosting a Lions team that barely survived its opener and now faces injury concerns on both sides of the ball. Kickoff is scheduled for 8:15 p.m. ET on Prime Video.

Both teams are 1–0. Buffalo beat Houston 36–31 behind four touchdowns from Josh Allen. Detroit needed overtime and a failed New Orleans two-point conversion to escape with a 31–30 victory after surrendering a 21-point lead.

Buffalo is a 4.5-point favorite, with the total at 53.5. The Bills have the better passing matchup, and Detroit’s offensive-line injuries could make keeping pace considerably harder.

The pick is Buffalo −4.5.

Lions vs. Bills Odds

Odds checked September 15. Prices vary at different sportsbooks.

Earlier listings had Buffalo closer to a field-goal favorite, so bettors backing the Bills now are paying more than those who got in early. That matters. A three-point Buffalo win would lose at the current spread.

There is still enough in the matchup to support laying 4.5, but this is a price-sensitive recommendation. The same argument becomes much less attractive if Buffalo approaches a touchdown favorite.

Josh Allen Has the Matchup Buffalo Wants

Detroit’s defensive problems did not begin with Sunday’s second-half collapse.

During his offseason review, defensive coordinator Kelvin Sheppard counted 105 explosive plays allowed in 2025, including 82 passes. Preventing those gains was a priority entering this season. Now the Lions are trying to make those corrections without safeties Brian Branch and Kerby Joseph, both of whom remain on reserve/PUP.

Allen is a demanding opponent for a secondary missing that much talent.

He completed 20 of 29 passes for 334 yards and two touchdowns against Houston, averaging 11.5 yards per attempt. Dalton Kincaid caught five passes for 130 yards. DJ Moore added five catches for 100 yards and a touchdown in his Buffalo debut.

The distribution is as important as the totals. Detroit cannot devote its entire coverage plan to one receiver. Moore can threaten downfield, Kincaid can work between defenders, and Khalil Shakir gives Allen another reliable option underneath.

Allen also scored twice on the ground. Defenders who turn their backs in coverage have to account for his ability to extend possessions with his legs.

Buffalo’s winning touchdown went to Joshua Palmer on a 34-yard pass with 1:36 remaining. Even after Houston held the Bills deep in their own territory late, Allen needed only one possession to overturn the game.

Detroit will have to defend the entire field.

Detroit’s 410 Passing Yards Allowed Need a Closer Look

Tyler Shough threw for 410 yards and three touchdowns against the Lions, but simply projecting that performance onto Allen would be careless. Shough attempted 56 passes, and overtime added another possession.

The more concerning detail is how Detroit lost control.

The Lions led 21–0 in the third quarter. New Orleans tied the game at 24 before the end of regulation, then answered Detroit’s overtime touchdown with another scoring drive. Only an incomplete two-point attempt prevented the Saints from leaving with a win.

Detroit forced three turnovers and still allowed 469 total yards.

That is an uncomfortable combination for anyone taking the points Thursday. The Lions cannot count on winning the turnover battle every week, especially against a Buffalo offense that committed none in Houston.

There is a counterargument. Aidan Hutchinson recorded two sacks in the opener, and Detroit has enough talent up front to disrupt Allen. The Lions’ chances improve considerably if they can generate pressure without exposing an already weakened secondary.

But pressure has to finish the play. Allen is particularly dangerous when the first rush gets close and the coverage breaks down behind it.

The Lions’ Offensive Line Could Decide the Bet

Detroit’s best protection against Allen is an offense that keeps producing first downs. That becomes harder if the Lions cannot get their preferred linemen on the field.

Monday’s estimated injury report listed left guard Christian Mahogany and right tackle Blake Miller as non-participants. Mahogany was listed with a hip injury, Miller with a knee injury. Center Juice Scruggs was limited by a knee issue.

The Lions held a walkthrough, so those designations were estimates rather than participation in a full practice. None should be confused with a final ruling for Thursday.

Still, the concern is substantial.

Miller expressed optimism about playing, while Dan Campbell indicated Mahogany could have a harder time getting ready. Ben Bartch replaced Mahogany against New Orleans. Larry Borom is available if Miller cannot play. With Cade Mays already on injured reserve, Detroit has less room for another problem at center.

Buffalo’s pass rush offers an immediate test. Greg Rousseau produced two strip-sacks against Houston, including the play that secured the victory. Deone Walker also recorded a sack.

If Detroit falls behind and has to throw repeatedly, those protection issues become more pronounced. Jared Goff can distribute the ball effectively when the offense stays on schedule. Asking him to overcome obvious passing situations behind a patched-up line is a tougher proposition.

Jahmyr Gibbs Is Detroit’s Best Answer

There is a reasonable case for the underdog, and it begins with Gibbs.

He rushed 29 times for 156 yards and two touchdowns against New Orleans. Detroit finished with 165 rushing yards at 5.0 per carry, establishing the physical offense Campbell wants.

With David Montgomery now in Houston and Isiah Pacheco on injured reserve, Gibbs is carrying a larger share of the backfield work. His ability to create yards gives Detroit a chance to keep the game within one score even if the defense struggles.

Buffalo’s defense was far from dominant in its opener. Houston gained 381 yards, collected 26 first downs and converted seven of 16 third downs. The Bills needed their pass rush to rescue them on the final possession.

The Texans also ran for 124 yards, although their 3.9-yard average suggests Buffalo’s run defense was more competitive than the raw total might imply.

For Detroit, the goal is sustained production. Productive runs can set up manageable third downs and give Goff opportunities to find Amon-Ra St. Brown, Sam LaPorta and Jameson Williams without obvious pressure situations.

That is why the offensive-line report matters so much. Detroit’s most promising way to cover depends on the health of the unit opening those running lanes.

Buffalo linebacker Terrel Bernard is another player to monitor after appearing as limited in Monday’s reporting. His availability matters against Gibbs and Detroit’s underneath passing game.

Don’t Bet the Stadium Celebration

The first regular-season game at the new Highmark Stadium will bring plenty of attention. OneRepublic is scheduled to perform at halftime, and Bruce Smith will be honored as the first Legend of the Game in the building.

The atmosphere should be lively. It should not be the main reason to lay points.

Buffalo’s advantages are more tangible: Allen against Detroit’s available defensive backs, multiple receiving threats and a pass rush facing an injured offensive line.

The new grass surface also deserves a final check. Buffalo replaced the initial field ahead of the opener after it failed to meet the team’s standards. That is worth monitoring during warmups, but there is no established reason to assume it will favor either team.

Both clubs face a short turnaround. Detroit played overtime Sunday and now travels. Buffalo returns from Houston. Neither team gets a comfortable preparation week.

Lions vs. Bills Total: Is 53.5 Too High?

The over is easy to understand.

Buffalo scored 36 in its opener. Detroit’s game finished with 61 combined points. Their last meeting, in December 2024, ended 48–42 in Buffalo’s favor.

But those results do not automatically make Over 53.5 a good bet.

Detroit and New Orleans were tied 24–24 after regulation. Overtime added 13 points. The Lions may also lean heavily on Gibbs, while offensive-line injuries could produce stalled possessions rather than a shootout.

Buffalo’s passing matchup supports another productive scoring night. Detroit’s ability to contribute its share is less certain.

The available Thursday-night forecast calls for mild temperatures, light wind and a slight shower chance. Weather does not currently provide a compelling reason to take the under, but the hourly forecast should be checked before kickoff.

My projection lands at 55 points. That is too close to 53.5 to justify a separate total bet.

Lions vs. Bills Prediction and Best Bet

Detroit has enough offensive talent to make Buffalo work. Gibbs can sustain drives, St. Brown remains a difficult assignment, and Hutchinson can create the kind of defensive play that changes a game.

Buffalo has more ways to win this particular matchup.

Allen enters off an efficient opener with Moore and Kincaid already producing. Detroit remains without Branch and Joseph, and its offensive line has multiple injuries to manage on short rest.

I expect the Lions to move the ball, but Buffalo should create more explosive gains and put Detroit into enough passing situations for its protection problems to matter.

Lay the 4.5 with Buffalo at −110 or better. If the spread climbs to −6 or higher, pass rather than chase the move.

Best bet: Buffalo Bills −4.5
Predicted score: Bills 31, Lions 24
Total: Pass at 53.5