The two-time tourist is set to retire from international rugby following the World Cup in September.
He had been due to face France in the Championship finale on Saturday but a knee injury suffered in the narrow victory over Ireland has ruled Williams out.
"Shane will be out of action for a period of six to eight weeks after sustaining damage to the posterior cruciate ligament in his left knee during the match at the weekend," said Wales' medical manager Prav Mathema.
"Thankfully there is no need for surgical intervention and he will now undergo a period of rehabilitation which will see him return to full fitness."
Wales coach Warren Gatland has already added Scarlets wing George North to his squad in advance of the trip to Stade de France and there are no further call-ups expected.
The Wales side to face France will now be named on Thursday, 17 March after Gatland took the decision to allow extra training time for players throughout his squad to make their bids for selection.
Following Wales' dramatic victory over Ireland Williams re-affirmed his desire to retire from international duty at the end of the season and that France would be his last Championship clash.
"It is a big year for me. I'll be 35 next year and there are younger boys pushing for my position," said Williams.
"I don't want to say I'll never play for Wales again after this year because, if need be, I'll be there.
"But I've got to be realistic. I'm a wing and you don't normally play on until you are 35 in that position and as far as I'm concerned this will be my last Six Nations.
"Maybe if I was a prop I'd have a few more left in me, but there is only so long you can be on top of your game at this level. It is ruthless."