McCoy suffered a rib injury in last week's 31-20 loss to the Los Angeles Chargers and was limited in practice all week.
The Bills have scored an AFC-low 23 points in a pair of lopsided losses, including a 47-3 mauling by the Baltimore Ravens in the season opener.
McCoy rushed for only 39 yards on nine carries against the Chargers and was limited to 22 yards on seven rushing attempts in Week 1. He has five catches for 28 yards in two games.
The absence of McCoy will put more of an onus on rookie quarterback Josh Allen. The No. 7 overall pick out of Wyoming, Allen was 18 of 33 for 245 yards with one touchdown and two interceptions in his first career start last week.
Buffalo's offense ranks 31st both in total yards per game (223.0) and passing yards per game (139.5).
If McCoy, who eclipsed 1,000 yards rushing for the sixth time in his career in 2017, is unable to go, Chris Ivory is expected to get the start in his place.
Ivory has only five carries for 10 yards on the season, but he rushed for more than 1,000 yards as recently as the 2015 season with the New York Jets and has averaged 4.4 yards for his career.