Rivera would not comment on specifics of the illness.
"I would say it's safe to rule him out," Rivera said on Wednesday after Samuel missed his third straight day of practice. "I'm not going to play around on this one. It's a medical issue, and the doctors are taking care of it for him.
"It's just unfortunate. I know he'll continue to do what he's told. He'll be back."
Among the six receivers who made the 53-man roster, Samuel led the team with 10 catches for 180 yards during the preseason. The 2017 second-round pick is expected to play a big role as a slot and speed receiver after missing much of his rookie year with injuries.
"So my mindset coming into this year is be the player I know I can be, play with confidence and show them why they drafted me," Samuel told ESPN.com last week. "Just be a baller. That's what I do."
It is uncertain how many games Samuel will miss beyond the opener.
"We'll see what happens," Rivera said. "He's in the doctor's care right now."
Quarterback Cam Newton said he was "saddened" to hear about Samuel's situation, adding "my prayers are with him." Starting wide receiver Devin Funchess said he was unaware of why Samuel had been out since Sunday until a reporter asked him about it on Wednesday.
Damiere Byrd, who made the roster as the sixth receiver, will see an increased role with Samuel out. Samuel also was being used on special teams as a returner.
"We've got a lot of supers in the room, a lot of people that can do different things," Funchess said. "One person doesn't make that room. One person doesn't make that team. We'll continue to be special with the guys we have."