The Raiders selected the 21-year-old University of Alabama product with the 12th overall pick in the 2020 draft.
He made a minor impact across the team's first two games with four catches for 59 yards. He also tallied two carries for 11 yards as Vegas attempted to use his game-breaking speed by designing some receiver runs in an effort to get him the ball in space.
Ruggs suffered the knee injury in the team's Week 1 win over the Carolina Panthers, but he didn't think it was serious and was happy with his initial involvement.
"I mean it was big for my first catch to be a big play and pretty much get the game started for the offense," he told reporters. "That was big for me because I want to be one of the guys that can be a spark whenever we need it."
The Raiders will also be without fellow rookie wideout Bryan Edwards against the Bills, per Rapoport.
Tight end Darren Waller is set to serve as quarterback Derek Carr's top target Sunday. Hunter Renfrow and Nelson Agholor will likely draw the start at receiver with Zay Jones and Rico Gafford providing depth.
Vegas will probably need its passing game to put up big numbers despite the absences as it faces a Bills offense that ranks fourth in yardage (434 YPG) and third in scoring (31 PPG).
Ruggs and Edwards' next chance to return would come Oct. 11 in a Week 5 clash with the reigning Super Bowl champion Kansas City Chiefs. The Raiders have a bye in Week 6 that will likely factor in to the team's decision-making process, though.