A pair of Super Bowl contenders face off at Highmark Stadium on Sunday, where the Buffalo Bills host the Philadelphia Eagles.
James Cook has been the best running back in the league over the last couple of months, and my Eagles vs. Bills predictions are backing him to have another big game in Week 17.
Here are my best NFL picks for this marquee matchup on December 28.
Eagles vs Bills prediction
Eagles vs Bills Best bet: James Cook Over 104.5 rushing + receiving yards (-110)
The Buffalo Bills could have a tough time throwing the ball against the Philadelphia Eagles. After all, Philly is fourth in the league in defensive pass DVOA and has a pair of Pro Bowl corners who can lock up Buffalo's mediocre receivers.
That should lead to the Bills leaning on Pro Bowl running back James Cook. Cook leads the NFL with 1,532 rushing yards while adding another 288 yards on 32 receptions.
The Eagles are 21st in the league in defensive rush success rate and rank 26th in receiving yards allowed to running backs.
In what is expected to be a close contest on a rainy December day in Buffalo, expect plenty of touches for Cook out of the backfield.
He has racked up at least 110 rushing and receiving yards in eight of his last nine games and should eclipse that mark again.
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Eagles vs Bills same-game parlay
Cook has also scored 14 touchdowns in 15 games, so let's add his anytime touchdown prop to this SGP.
While I'm betting on a big game from Cook, I'm also expecting a strong performance from Eagles RB Saquon Barkley. Last year's NFL Offensive Player of the Year struggled at the start of the season but has picked up steam, rumbling for more than 120 yards in two of the last three weeks.
Buffalo has been terrible against the run, ranking 31st in defensive rush EPA while allowing 144.0 rushing yards per game.
Eagles vs Bills SGP
- James Cook Over 104.5 rushing + receiving yards
- James Cook anytime touchdown
- Saquon Barkley Over 84.5 rushing yards
Our big-ticket SGP: Barkley finds the Paint!
Let's go all out on these running backs and also back Barkley to score a touchdown since the Bills have allowed a league-high 18 rushing TDs.
Eagles vs Bills SGP
- James Cook Over 104.5 rushing + receiving yards
- James Cook anytime touchdown
- Saquon Barkley Over 84.5 rushing yards
- Saquon Barkley anytime touchdown
Eagles vs Bills odds
- Spread: Eagles +1.5 (-110) | Bills -1.5 (-110)
- Moneyline: Eagles +102 | Bills -120
- Over/Under: Over 44.5 (-105) | Under 44.5 (-115)
More NFL picks and odds from Covers
Eagles vs Bills trend to know
The Bills have covered the second-half spread in eight of their last 10 games at home (+5.50 Units / 47% ROI). Find more NFL betting trends for Eagles vs. Bills.
How to watch Eagles vs Bills
| Location | Highmark Stadium, Orchard Park, NY |
| Date | Sunday, December 28, 2025 |
| Kickoff | 4:25 p.m. ET |
| TV | FOX |
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