Lions vs Bills NFL Picks and Predictions

The Detroit Lions travel to Buffalo to open the Thursday night slate of NFL Week 2, and our Lions vs Bills predictions lean on HOF's full team, player, and betting data to break down the matchup. Buffalo is favored at home, but Detroit's offensive numbers give it a case in a handful of key statistical categories. Below, we cover the Lions vs Bills picks for the spread, moneyline, and total, along with the individual player matchups worth tracking on Thursday Night Football — and for the full slate of kickoff times and lines, see our Week 2 NFL Schedule.

Lions vs Bills Odds and Spread

Buffalo opened as a 3.5-point favorite at home (-105), with Detroit getting the same 3.5 points at -110. On the moneyline, the Bills are priced at -162 and the Lions sit at +164, while the total is set at 52.5 (over -105, under -110) — one of the higher totals on the Week 2 board. For the most current numbers before kickoff, check a sports betting research app to compare the Lions vs Bills best odds across books.

Detroit has covered as a spread underdog of 3.5 points or fewer in 59% of qualifying games over HOF's tracked sample, while Buffalo has covered as a similar-sized favorite in 53% of its games. On the total, Buffalo's recent games have leaned toward the under, hitting in 74% of its tracked sample, while Detroit's own total trend runs closer to even. That split is worth watching against a 52.5 number that projects a competitive, higher-scoring game.

Lions vs Bills Team Comparison

HOF's team data shows the Lions offense ranked 3rd in the league in total rush-and-receiving yards (386.2 per game) and 3rd in anytime touchdowns (3.3), while Buffalo's defense ranks 6th in yardage allowed (289.5) and 20th in touchdowns allowed (2.5). The split is more pronounced by phase: Detroit's passing offense (3rd, 253.1 yards) draws a difficult matchup against a Bills defense that ranks 2nd against the pass (165.9 allowed), but the Lions' running game (13th, 121.1 yards) lines up far more favorably against a Buffalo run defense that ranks just 28th in yards allowed (135.2) and 30th in rushing touchdowns allowed (1.3). That gap suggests Detroit's clearest path to points on Thursday night runs through the ground game rather than forcing the ball downfield against Buffalo's top-tier secondary.

Quarterback Matchup: Goff vs Allen

Jared Goff carries a difficult matchup grade against Buffalo in HOF's player data, projected for 293.3 passing yards, 1.9 passing touchdowns, and 0.5 interceptions — a big workload that reflects how often Detroit may need to throw to keep pace on the road. Josh Allen grades out with a more favorable matchup, projected for 231.7 passing yards, 1.6 touchdowns, and 0.8 interceptions, a turnover projection a touch above his typical form. If Allen's number holds, it could open the door for Detroit's defense to force the extra possession it may need to stay competitive.

Key Players to Watch

Jahmyr Gibbs profiles as Detroit's best individual matchup, projected for 111.9 total yards and 1.1 touchdowns against a favorable Buffalo run defense, while Bills lead back James Cook projects for 106 total yards and 0.7 touchdowns in a tougher spot. Backup Ray Davis adds a change-of-pace look for Buffalo, projected for 55.3 total yards and 0.2 touchdowns.

In the passing game, Amon-Ra St. Brown leads all Lions vs Bills pass catchers in usage with a 31.3% target share (10.1 targets per game) even though his individual matchup grade is difficult, and Jameson Williams is next at 18.4% of the target share. For Buffalo, Khalil Shakir leads the way with a 22.1% target share and the best matchup grade of the Bills' receiving corps, projected for 46.6 total yards, while Dalton Kincaid (14.7%) and Keon Coleman (14.3%) round out the primary passing-game options.

For a deeper breakdown of these usage rates and how they translate into player-specific betting angles, see our Lions vs Bills player props coverage.

Injury Report

On the Detroit side, I. Pacheco (back) and B. Branch (surgery) are both listed as out, with K. Law (knee) also out. Buffalo is missing T. Shavers (surgery), while T. Johnson (lower leg) and J. Hancock (quadriceps) both carry questionable tags heading into Thursday and are worth checking again closer to kickoff, since either absence would shift usage rates for Buffalo's remaining pass-catching group.

Lions vs Bills Prediction

Weighing the matchup data together, Buffalo's home-field spot, the tougher passing-down matchup for Goff, and the stronger historical cover rate point toward the Bills at -3.5. Detroit's advantage in the running game and its strong anytime-touchdown rate keep the Lions live enough to cover, especially if Allen's turnover number ticks up as projected. The total sits at one of the week's higher marks at 52.5, and with both offenses carrying top-five marks in several statistical categories, there's a case for the over even with Buffalo's recent trend toward the under.

That combination of team and player trends is why Buffalo grades out as the top of our Lions vs Bills NFL predictions and one of our Lions vs Bills best picks on the Week 2 board, though Detroit's rushing edge keeps this from being a lopsided Lions vs Bills NFL picks call against the spread. These are analytical leans based on the data above, not guarantees, so track any line movement before placing a wager.