Lions vs. Bills Prediction: Week 2 Odds, Picks, Best Bet & Betting Splits (Sept. 17)
Last Updated: September 20, 2026 4:21 PM EDT • 2 minute read X Social Google News Link
Two Super Bowl contenders collide at the new Highmark Stadium on Thursday Night Football, and I’m backing Josh Allen and the Bills in my Lions vs. Bills prediction.
Detroit escaped with a narrow Week 1 win over the Saints, but its performance left plenty to be desired. Buffalo, meanwhile, looked much sharper in its season opener. That contrast is reflected in the market, as the Bills are listed as a 4.5-point betting favorite, with kickoff in Orchard Park, N.Y., set for 8:15 p.m. ET (Prime Video).
🏈 Lions vs. Bills picks & predictions
See all of our experts' NFL picks for Week 2 based on the latest NFL odds.
Total wagered: 1.5 units | Max profit: +1.36 units
💰 Lions vs. Bills prediction & best bet
Bills -4.5 (-110)
The Bills erupted for 36 points against a Houston Texans team that had the second-best defensive DVOA last season.
In the process, Allen got a gigantic monkey off his back in beating the Texans for the first time.
He’ll enter Thursday’s tilt brimming with confidence, especially as he faces a Lions secondary that was ripped apart in the second half at home against the New Orleans Saints.
Tyler Shough racked up 410 passing yards and three TDs in the 31-30 defeat.
Other than escaping with the win and Jahmyr Gibbs’ sensational performance, there wasn’t much to like about the Lions' Week 1 win.
📡 SBR Edge
Allen is 10-1 in September as a home betting favorite and 7-0 in the previous seven games. It’s also opening night for the new Highmark Stadium.
Lions secondary reeling entering TNF
The Lions’ top two safeties, Brian Branch and Kerby Joseph, will miss at least the first four games. And their absence in Week 1 was more noticeable than Dan Campbell’s second-half rage.
Detroit has another injury concern heading into TNF, with starting cornerback DJ Reed sustaining a foot injury.
He’s limited in practice and will likely be a game-time decision. Even with Reed, the Lions' secondary was leakier in Week 1 than a collection of open manholes, with the Saints’ Chris Olave posting a career-high 182 receiving yards on 10 receptions, representing another prime example.
Score prediction: Bills 31, Lions 24
📊 Lions vs. Bills odds
See the latest NFL odds for every Week 2 matchup.
Lions vs. Bills opening odds
- Moneyline: Lions +140 | Bills -165
- Spread: Lions +3 (-115) | Bills -3 (-105)
- Over/Under: Over 52.5 (-115) | Under 52.5 (-105)
🎟️ Lions vs. Bills betting splits
Betting insights via BetMGM.
| Team / bet type | Odds | Bet % | Handle % |
|---|---|---|---|
| Lions | |||
| ⚪ Moneyline | +190 | 40% | 24% |
| ⚪ Spread | +5.5 | 42% | 36% |
| ⚪ Total | o55 | 62% | 74% |
| Bills | |||
| 🔴 Moneyline | -235 | 60% | 76% |
| 🔴 Spread | -5.5 | 58% | 64% |
| 🔴 Total | u55 | 38% | 26% |
📺 How to watch Lions vs. Bills: Week 2
- Date: Thursday, Sept. 17
- Kickoff: 8:15 p.m. ET
- Location: Highmark Stadium (Orchard Park, N.Y.)
- TV: Prime Video
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