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The Detroit Lions and Buffalo Bills will do battle at 8:15 p.m. ET on Thursday, September 17 on Prime Video. The Bills enter Thursday’s prime-time contest as a 5.5-point favorite on the spread, via PrizePicks.
The Bills began the 2026 season with a hard-fought 36-31 win against the Houston Texans in Week 1. Meanwhile, the Lions outlasted the New Orleans Saints 31-30 in overtime to begin the new campaign on a strong note.
Below, we'll break down our Lions vs. Bills prediction on the spread for Thursday Night Football in NFL Week 2.
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Lions vs. Bills Prediction, Spread, Over/Under – Thursday, September 17
Week 2 gets underway with an intriguing interconference showdown between two electric offenses.
In their most recent meeting in 2024, Buffalo beat Detroit 48-42 at Ford Field in a game where the Bills were 2.5-point favorites. QB Jared Goff led the Lions with 494 passing yards and 5 TDs, while WR Amon-Ra St. Brown caught 14 passes for 193 yards and a TD.
Still, Bills QB Josh Allen got the last laugh, accounting for 4 total TDs (2 passing & 2 rushing) on the day.
The Lions have covered the spread in two of the last three matchups against the Bills. Meanwhile, Buffalo is 2-3 against the spread in its last five home games.
Detroit will be without RB Isaiah Pacheco, who will likely be out until December due to a back injury. Meanwhile, C Juice Scruggs doesn’t carry an injury designation after logging a full practice on Wednesday. CB D.J. Reed is being listed as questionable with a foot injury.
When it comes to Buffalo, LBs Terrel Bernard (calf) and Bradley Chubb (thumb) don’t have an injury designation after practicing in full capacity this week. However, S Cole Bishop is listed as questionable with groin and knee injuries.
Lions vs. Bills Spread, Over/Under – Thursday, September 17
The Bills enter Thursday’s game as 5.5-point home favorites against the Lions, returning a 1.38x payout if they win outright, via PrizePicks.
Here are the full payouts for the Lions vs. Bills game on PrizePicks.
Make your Lions vs. Bills prediction on the spread on PrizePicks.
PrizePicks data is live at the time of writing and is subject to change.
Lions vs. Bills Prediction on Spread for TNF in NFL Week 2: 9/17/26
Here are the key game stats and trends behind our Lions vs. Bills prediction on the spread for Thursday, September 17.
- The Bills were 4-5 against the spread at home throughout the 2025 season.
- According to RBSDM, the Lions ranked 13th in offensive success rate (46.9%) in Week 1, while the Bills were 21st with a 41.8% offensive success rate.
- Meanwhile, the Bills recorded a 48.1% defensive success rate against the Texans, which ranked 24th in the NFL.
- After the Lions traded RB David Montgomery to the Texans in the offseason, RB Jahmyr Gibbs received the bulk of the carries out of Detroit’s backfield. In Week 1, Gibbs toted the ball 29 times for 156 yards (5.4 yards per carry) and 2 TDs.
- According to SumerSports, the Bills ranked 26th in EPA per rush (0.12) when defending the run against the Texans in Week 1.
- St. Brown had the third-highest target share (35.9%) in Week 1 and caught 10 passes for 69 yards and 2 TDs vs. the Saints.
- The Bills allowed a 0.04 EPA per pass play last weekend, ranking 19th leaguewide.
- In the turnover department, Detroit posted a +4 differential in 2025, good for ninth in the sport.
For TNF, PrizePicks has a Flash Sale on Bills WR DJ Moore. The Buffalo newcomer's receiving yards projection is still decreased from Taco Tuesday, lowering his projection from 57.5 to 34.5.
Use PrizePicks promo code PLAYBOOK for Bills vs. Lions. Play $5, Get $150 as a new user for Thursday Night Football.
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The Bills and Lions both started 2026 on the right foot, landing in the win column in Week 1. Now, Detroit will look to spoil Buffalo’s regular-season debut at Highmark Stadium on Thursday.
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