Watkins was listed as questionable on the injury report but coach Rex Ryan said on Friday that Watkins' chances of playing were "probably not real good."
Without Watkins, the Bills are expected to start fourth-year wideout Marquise Goodwin in his place, while veteran Greg Salas (questionable, groin) could also see increased playing time if he is active. Goodwin caught an 84-yard touchdown pass in the Bills' Sept. 15 loss to the New York Jets, and Salas caught a 71-yard touchdown in that game.
Watkins might have aggravated his surgically-repaired foot when he was stepped on during a walkthrough practice this week.
"I know it's a pain deal, there's no doubt about that," coach Rex Ryan said Friday. "I think he got stepped on during a walkthrough, so that probably never helped him."
Ryan said he didn't know exactly when the injury happened, and Watkins wasn't in the locker room Friday while reporters were present.
Watkins did not participate in any of the Bills' four practices this week. However, Ryan does not require his players to practice in order to play.
"If he feels good and he's up to it, then we'll put him in there," Ryan said Friday. "If a guy's that good, we'll play him."
Wide receiver Robert Woods said Friday that he noticed his teammate was in pain.
"I just saw it in his face," said Woods, who also didn't know when the injury occurred. "He made a little face. It bothered him, whatever it was."
Watkins started and played 40 snaps in the Bills' loss to the Jets after being listed as questionable on the injury report. He has six catches for 63 yards this season.