Lions at Bills Predictions, Odds and Betting Picks
The Buffalo Bills -3.5 is the starting point for Thursday night's matchup against the Detroit Lions. Buffalo has the biggest defensive personnel edge with Detroit missing safeties Brian Branch and Kerby Joseph, while the Lions face a short week after a 31-30 overtime win.
The total is 52.5 points at FanDuel Sportsbook, but rain and a 50% to 70% chance of scattered thunderstorms are forecast for Orchard Park. That weather, combined with Detroit's defensive injuries, shapes the strongest NFL Picks for the game.
Lions vs Bills Game Preview
Detroit enters Week 2 at 1-0 after beating New Orleans 31-30 in overtime. Jared Goff threw for the Lions in that game, while Josh Allen led Buffalo to a 36-31 road win over Houston. The Bills and Lions both scored at least 31 points in Week 1, but Detroit also allowed 30 points before overtime.
The biggest roster issue is on Detroit's defense. Branch and Joseph remain on the reserve/PUP list, while Christian Izien is questionable with a groin injury and Christian Mahogany is dealing with a knee and hip issue after Week 1. Buffalo reported no major fresh injuries from its opener, giving Allen a healthier supporting group for the regular-season debut at New Highmark Stadium.
Lions vs Bills Moneyline Pick
Take the Buffalo Bills moneyline at -196. Allen faces a Detroit secondary without Branch and Joseph, giving Buffalo a clear matchup advantage against a defense that allowed 30 points in Week 1. The Bills also have home-field advantage for the opening regular-season game at their new stadium.
The -196 price is expensive, so bettors should compare the number across the best NFL betting sites before placing a real-money wager. The strongest NFL Picks favor Buffalo because the injury situation and home setting give the Bills a more stable setup than Detroit.
Pick: Buffalo Bills ML (-196 at FanDuel Sportsbook).
Against the Spread Pick
Take Buffalo Bills -3.5 at -110. The number sits just above the key number of 3, so Buffalo needs to win by at least four points for the spread ticket to cash. Detroit's 31-30 overtime win shows the Lions can stay close in a high-scoring game, but their defensive absences make a four-point loss more likely.
The margin case also comes from the schedule. Detroit played a 61-point overtime game on Sunday and now travels to Buffalo on Thursday, leaving only a few days to recover and prepare. Those Trends in NFL team performance favor the home side when the bet requires Buffalo to create separation rather than simply win.
Pick: Buffalo Bills -3.5 (-110 at FanDuel Sportsbook).
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Lions vs Bills Game Total Pick
Take the Under 52.5 at -110. Detroit scored 31 points in Week 1, but the Lions needed overtime to reach that mark, while Buffalo's defense held Houston to 31 points in a 36-31 road victory. The 52.5 total also requires both offenses to maintain a strong scoring pace for four quarters.
Weather is another factor supporting the Under. Forecasts call for temperatures around 55°F to 58°F with a 50% to 70% chance of scattered thunderstorms and evening rain. Wet conditions can hurt footing and passing efficiency, making the Under one of the stronger NFL Picks at the current number.
The weather also separates these NFL predictions from a simple box-score approach. Both teams scored 31 or more points in Week 1, but the forecast gives the total a different setup for Thursday night.
Pick: Under 52.5 (-110 at FanDuel Sportsbook).
How to Watch Detroit Lions vs Buffalo Bills and Game Info
- Location: New Highmark Stadium, Orchard Park, NY
- Date: Thursday, September 17, 2026
- Kickoff: 8:15 p.m. ET
- TV: Amazon Prime Video
- Detroit Lions starting quarterback: Jared Goff.
- Buffalo Bills starting quarterback: Josh Allen.
- Weather forecast: 55°F to 58°F, scattered thunderstorms and evening rain, wind direction and speed TBD.
Final Takeaways
The Bills offer the stronger betting spot with home-field advantage, a healthier roster and a Detroit secondary missing Branch and Joseph. The best NFL predictions are Buffalo moneyline at -196, Buffalo -3.5 and Under 52.5. The strongest Trends in NFL team performance angle is the contrast between Detroit's overtime game and Buffalo's regulation win, while the weather adds support to the Under. These NFL Picks all point toward Buffalo controlling the matchup without needing a shootout.
All odds as of 5:51 a.m. ET on September 14, 2026. Odds sourced from FanDuel Sportsbook. Check the latest odds and line movement for Detroit Lions vs Buffalo Bills at betting.net before placing your bets.