"Will Sammy play? I'm not sure," Ryan told reporters Wednesday. "Shady doesn't look good."
Later, in an appearance on WFAN radio in New York, Ryan indicated he was less optimistic about either player's chances Sunday.
"Well, I mean... I'm telling everybody, 'Oh yeah, he's got a great chance,'" Ryan said of McCoy. "But we all know he doesn't. And the same thing with Sammy Watkins. Will he play? Probably not."
Neither player practiced Wednesday, and Ryan told reporters that McCoy is "certainly not 100 percent" and that "there is a real possibility that he won't play in this game."
ESPN NFL Insider Adam Schefter reported Monday that the Bills could rest McCoy until his hamstring injury, which has lingered over the first three weeks of the season, is fully healed.
"Get him healthy," Ryan said Wednesday. "He's obviously a super talent. Sometimes a guy like that who's less than 100 percent is still pretty darn good, but is it worth the time to get him at 100 percent or near 100 percent? That's something we're weighing right now."
The play of rookie Karlos Williams, who leads the NFL with an average of 7.75 yards per carry, has made the Bills more comfortable resting McCoy, who was limited to 16 yards on 11 carries in the Bills' 41-14 win over the Miami Dolphins last Sunday.
"I was never really effective today like I wanted to be," McCoy said in the locker room after the game. "Just trying to go. I can't really go like I want to."
Giants coach Tom Coughlin said Tuesday that his team will be prepared for whichever running back is in the Bills' backfield Sunday.
"It won't change," Coughlin said of his plans. "You know the different styles of the two runners; obviously, they're a little bit different. We know LeSean very well, and he's an excellent runner, always had significant days against us. But Williams is a powerful guy, a bigger guy, a slam it up in there, north and south guy. He has the speed to get outside, he's 4.48. Got to defend it all."
Watkins left Sunday's game in the first quarter and did not return. The fourth overall pick in 2014 underwent offseason hip surgery and missed the final three preseason games with glute and hamstring issues.
"Part of when he had the surgery, it takes away a little bit of your conditioning," Ryan told reporters Wednesday. "He has the pull in camp, misses time. Now he's coming back and he's got something else. It's just one of those things."
ESPN Staff Writer Dan Graziano contributed to this report.