Lions vs Bills Predictions, Picks, Odds & Betting Guide
NFL Week 1 was about as explosive as it gets, delivering a record amount of points, some unforgettable plays, and some wild finishes. What will Week 2 bring us to follow it up? Well, things get started with one heck of a matchup, as the Detroit Lions and Buffalo Bills lock horns on Thursday Night Football, with kickoff set for 8:15 PM ET live on Amazon Prime Video. Both the Lions and Bills scored over 30 points in their opening games and saw shootouts go down to the wire. Given the talent on both offenses, we may see the same here tonight.
We've got everything you need to bet on Lions vs Bills in our handy betting guide. You can get our expert NFL picks on the side and total for this matchup - along with every game throughout the entire season - plus Prop Holliday's best NFL player prop bets, JutPicks' anytime touchdown scorer predictions, and even a Lions vs Bills Same Game Parlay! Let’s break it all down.
Lions vs Bills Latest Odds
Odds courtesy of bet365 and available at 8:00 AM ET on Thursday, September 17. Find out the latest NFL odds for every Week 2 matchup.
Money Line: Lions (+195) vs Bills (-240)
Point Spread: Lions +5.5 (-110) vs Bills -5.5 (-110)
Game Totals: Over 54.5 (-120), Under 54.5 (+100)
Lions vs Bills Predictions & Picks
Chris Farley’s Lions vs Bills spread pick: Bills -5.5 (-110)
This is a short week for both programs, but the Bills return home with renewed confidence in their new regime and an offense that looks as explosive as it ever has. The Lions’ defense will be in a very vulnerable spot on the road after barely surviving against the Saints. All Bills for me.
Chris Farley’s Lions vs Bills total prediction: Over 54.5 (-105)
Whenever a total climbs and we see inflation like this, we look for reasons for why it might regress. In this case, the evidence supports another high-scoring affair. The Bills' offense looks as hot as ever, while the Lions will need to keep scoring to have any chance here. Expect fireworks on TNF.
Read NFL pro bettor Chris Farley’s full analysis for his Lions vs Bills TNF picks tonight, including a 5-star best bet
Lions vs Bills Player Prop Bets
Best Lions vs Bills player prop bet: Jameson Williams (DET) 50+ Receiving Yards (-150)
What makes me bullish on Williams in Week 2 is that he had 36% first-read target share (vs 18.6% in 2025). They are actively trying to get him the ball this season, and the Bills' defense gave up 160 air yards compared to the Saints' 109.
Get the full breakdown for Prop Holliday's best Lions vs Bills player prop bets, including an additional pick at +310 odds!
Lions vs Bills TD scorer best bet: Amon-Ra St. Brown (DET) anytime touchdown scorer (+115)
Amon-Ra St. Brown started his 2026 campaign with a stat-stuffing performance. He found the end zone twice, both within the red zone. The Bills' secondary was torched in Week 1, allowing C.J. Stroud to throw for 274 yards, and more importantly, Nico Collins to erupt for 75 yards on seven receptions and a touchdown.
JutPicks nailed a +350 touchdown winner on TNF last week, and is back here with his Lions vs Bills TD scorer best bets, featuring St. Brown and another pick at +650!
Detroit Lions vs Buffalo Bills Same Game Parlay
Bills -4.5 over Lions (-120)
Each team came out on the right end of a high-scoring thriller this past weekend, but Buffalo was far more impressive in the process. Josh Allen and company had to face Houston on the road, and the Texans arguably boasted the best defense in all of football last season. The visitors promptly racked up 409 total yards of offense on 7.9 yards per play. They did not commit a single turnover while forcing two. That is bad news for the Lions, who just barely beat the Saints at home despite the fact that New Orleans turned the ball over three times.
DJ Moore (BUF) Over 61.5 Receiving Yards (-110)
Not only are the Bills playing in a new stadium, but they also have a new head coach in offensive guru Joe Brady and a new receiver in DJ Moore. Early returns on all fronts are encouraging. Even against one of the best defenses in the NFL, Buffalo’s offense looked like a juggernaut in Week 1. Allen threw for 334 yards, 100 of which went to Moore on five receptions. Now they get to face a Detroit defense that got torched by second-year QB Tyler Shough and a New Orleans attack that pales in comparison to that of Buffalo.
Jared Goff (DET) 300+ Passing Yards (+192)
This play actually correlates quite nicely with Buffalo winning and covering, because Goff will have to air it out early and often if his team is playing from behind. The former #1 overall pick (2016) did not do a whole lot against New Orleans, but that was because Detroit led basically the entire game before collapsing late in regulation. As such, Jahmyr Gibbs got 29 carries. Expect fewer rushing attempts for Gibbs and more passes by Goff when the Lions visit Orchard Park.
Lions vs Bills SGP odds: +950
Get NFL Week 2 started right with our expert's Lions vs Bills Same Game Parlay at +950 odds
NFL Week 2 Picks
Check out our expert NFL predictions for the Week 2 matchups below:
