Williams, 28, had been trying to play through a torn shoulder labrum, but a source told ESPN's Adam Schefter on Tuesday that Williams will have surgery and will be sidelined for six months, effectively ending his season before it begins.
With Williams out, Las Vegas could potentially start two rookies at receiver in No. 12 overall selection Henry Ruggs III and third-round draft pick Bryan Edwards. It would be just the second time in franchise history the Raiders would start two rookie wideouts, as they also did it in 2009 with Darrius Heyward-Bey and Louis Murphy.
The Raiders also have veteran free-agent signee Nelson Agholor and returner Zay Jones, both of whom have impressed in camp and are the only two wideouts on the roster with more than 100 career catches, as well as slot man Hunter Renfrow, speedster Rico Hines, Marcell Ateman and Keelan Doss.
Williams, meanwhile, joined the Raiders on a four-year, $44 million free-agent contract with a max value of $47 million and $22 million guaranteed in 2019. He started off hot with touchdown catches in each of his first five games with the Raiders.
But plantar fasciitis in both feet slowed him, as he missed two games with the issues. Williams' 42 catches and 651 receiving yards both marked the second fewest of his five-year career.
Early in camp, Williams spoke of overcoming the issues with his feet.
"It took a pretty long time into the offseason to finally start feeling better," he said. "With the virus and stuff, I was able to even take more time, which was really helpful.
"I do a lot of daily maintenance stuff before and after practice to make sure that it doesn't come back. ... I've tried a million different things, and now I'm just starting to continue to add stuff, whatever feels good and however I can keep it that way into the next day and keep the soreness and all that stuff away. Honestly, I don't really know what it was that got me over that hump, but I'm just glad to be feeling better."