Thursday Night Football will make history in Week 2, with the Buffalo Bills playing their first regular-season game at the new Highmark Stadium.
The Bills will host the Detroit Lions in Orchard Park, giving us a primetime matchup between two teams that opened the 2026 season with wins. Buffalo came away with a 36-31 road victory over the Houston Texans, while Detroit survived the New Orleans Saints 31-30 in overtime.
There should be no shortage of star power, with Josh Allen leading a Bills offense featuring James Cook and D.J. Moore, while Jared Goff, Jahmyr Gibbs, and Amon-Ra St. Brown headline the Lions. The matchup kicks off Thursday, Sept. 17 at 8:15 p.m. ET on Prime Video, with Buffalo officially opening its new home under the lights.
Below, I’ll take a look at the latest Lions vs. Bills odds and make my TNF predictions for Week 2.
Updated TNF Odds Comparison
All NFL odds referenced for these TNF Week 2 predictions are current as of Thursday, Sep. 17, and courtesy of DraftKings Sportsbook.
TNF Implied Score & Team Totals
Bills 30, Lions 24.5
Buffalo is projected to score 30 points at home, and Detroit’s injury issues in the secondary help explain the high team total. The Lions are without starting safeties Kerby Joseph and Brian Branch, who are both on the reserve/PUP list and must miss at least the first four games. Joseph is still recovering from the knee injury that cost him the final 11 games of last season, while Branch is working his way back from a torn Achilles suffered in December. Starting cornerback D.J. Reed is also questionable with a foot injury.
That is a difficult situation against Josh Allen and a Buffalo offense that scored 36 points in Week 1. Allen accounted for 357 total yards and four touchdowns against Houston, while Detroit allowed Saints quarterback Tyler Shough to throw for 410 yards in its opener. The 30-24.5 team-total split reflects the expectation that Buffalo can take advantage of Detroit’s depleted secondary, although Jared Goff, Jahmyr Gibbs, and Amon-Ra St. Brown give the Lions enough offensive firepower to keep pace.
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Thursday Night Football Prediction
TNF Score Prediction: Bills 35, Lions 21
Detroit enters this matchup in a difficult spot because of injuries on both sides of the ball. The Lions are already without starting safeties Kerby Joseph and Brian Branch, who remain on the PUP list with knee and Achilles injuries, respectively. Starting cornerback D.J. Reed is also questionable with a foot injury. That depleted secondary gave up 410 passing yards to Tyler Shough in Week 1, and now it has to deal with Josh Allen.
The offensive line is also banged up. Starting right tackle Blake Miller has been ruled out with a knee injury, while starting left guard Christian Mahogany will miss the game because of a hip issue. That leaves Detroit short-handed up front against a Buffalo defense that recorded three sacks, nine quarterback hits, and eight tackles for loss against Houston.
Those injuries are especially concerning because Buffalo’s offense looked terrific in its 36-31 win over the Texans. Allen threw for 334 yards and two touchdowns while adding 23 yards and two more scores on the ground. Dalton Kincaid went for 130 receiving yards, while D.J. Moore added 100 as Buffalo consistently pushed the ball downfield.
Detroit still has enough playmakers with Jared Goff, Jahmyr Gibbs, Amon-Ra St. Brown, and Jameson Williams to put points on the board, but I’m not confident that its depleted roster can keep up for four quarters. Look for Allen to attack Detroit’s weakened secondary while Buffalo’s defensive front takes advantage of an injury-riddled offensive line, allowing the Bills to pull away for a 35-21 win.
Thursday Night Football Bet Tips
Keep these Thursday Night Football bet tips and trends in mind before making your Lions vs. Bills best bets.
- Teams coming off an overtime game on a short week have struggled badly on Thursday Night Football, going just 6-25 ATS since 2000. Detroit needed overtime to beat New Orleans 31-30 on Sunday and now has to travel to Buffalo only four days later.
- The short turnaround is even more concerning because Detroit is dealing with several important injuries. Starting offensive linemen Christian Mahogany and Blake Miller have been ruled out, while cornerback D.J. Reed is questionable with a foot injury. The Lions are also already without starting safeties Kerby Joseph and Brian Branch, leaving them thin in the secondary against Josh Allen.
- Buffalo was more aggressive through the air in Week 1, with Allen attempting 29 passes for 334 yards and two touchdowns against Houston. James Cook was held to 57 rushing yards, while Dalton Kincaid went for 130 receiving yards and D.J. Moore added 100. That approach could continue against a Detroit secondary missing Joseph and Branch, especially after the Lions allowed Tyler Shough to throw for 410 yards in Week 1.
Thursday Night Football Best Bets
TNF Over/Under Pick: Lions @ Bills Under 54.5 Points (+100)
This total feels a little too high, especially with Detroit entering the game short-handed on both the offensive line and in the secondary.
Buffalo should have plenty of opportunities to score against a depleted Lions defense, but that does not necessarily mean we get a back-and-forth shootout. If the Bills build an early lead, Detroit could have trouble keeping pace, particularly with its offensive line missing multiple starters.
That also creates a path for Buffalo to become more conservative in the second half. The Bills can lean on James Cook, shorten the game, and avoid exposing Josh Allen to unnecessary hits if they are playing from ahead.
A score like 35-17 or 34-20 would still qualify as a comfortable Buffalo win while staying below this number. With 54.5 requiring both offenses to contribute heavily, I prefer the Under as my NFL pick of the day for Thursday Night Football.
TNF Pick Against the Spread: Bills -5.5 (-110)
Buffalo opened as only a 3.5-point favorite, but the line has already moved to -5.5, and I still think this is a strong spot to back the Bills.
Detroit is dealing with significant injuries on both sides of the ball, including multiple starters in the secondary and along the offensive line. That is a tough setup on a short week against Josh Allen and a Buffalo offense that looked sharp in Week 1.
The Bills also have the advantage of playing at home in the first regular-season game at the new Highmark Stadium, which should create an especially strong atmosphere for the home opener.
Even after the move from -3.5 to -5.5, I’m comfortable laying the points. Buffalo has a clear path to creating separation if Detroit struggles to protect Jared Goff or contain Allen through the air, making Bills -5.5 my preferred spread bet for Thursday Night Football.
Thursday Night Football Prop Bet
TNF Prop: Josh Allen Over 250.5 Passing Yards (-111)
Buffalo showed a much more aggressive passing approach in Week 1, with Josh Allen throwing for 334 yards and two touchdowns against a strong Houston defense.
That fits with what we’ve heard from Joe Brady since taking over as head coach and retaining play-calling duties. Buffalo wants to put the ball in Allen’s hands and create more explosive plays through the air, which was evident when he averaged 13.2 air yards per attempt and completed five passes of at least 30 yards in the opener.
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The matchup is also ideal. Detroit is without starting safeties Kerby Joseph and Brian Branch, while D.J. Reed is questionable with a foot injury. The Lions allowed Tyler Shough to throw for 410 yards and six completions of at least 20 yards in Week 1.
With D.J. Moore and Dalton Kincaid both coming off 100-yard games and Buffalo showing a willingness to attack downfield, Allen should have plenty of opportunities against this depleted secondary. I like the Over on 250.5 passing yards for Thursday Night Football.
Thursday Night Football Parlay
Best TNF Same-Game Parlay (+162)
- Bills ML (-250)
- Under 54.5 (+100)
I already like Buffalo -5.5 as my spread pick, so using the moneyline here gives me some protection in case the Bills control the game without winning by a full touchdown.
Detroit enters this matchup extremely short-handed, especially in the secondary and along the offensive line. The Lions are already without Kerby Joseph and Brian Branch, while D.J. Reed is questionable, and they will also be missing starting offensive linemen Christian Mahogany and Blake Miller.
Those injuries give Buffalo a clear path to controlling this game. Josh Allen should be able to attack Detroit’s depleted secondary, while the Bills’ defense can take advantage of an offensive line that is missing multiple starters.
The Under fits with the possibility that this turns into a Buffalo blowout rather than a shootout. If the Bills build a comfortable lead, they can lean more heavily on James Cook and the running game in the second half, shortening the game and limiting Detroit’s possessions.
Combining Bills ML with Under 54.5 gives us a way to back Buffalo while accounting for a game script where the Bills pull away and Detroit struggles to contribute enough points to push the total Over.
