Webb's absence follows hot on the heels of fullback and key goalkicker Leigh Halfpenny who will also miss the Sept.18-Oct.31 showpiece with a knee injury.
Both were hurt in the weekend win over Italy, Wales' final World Cup warm-up before they start their campaign against Uruguay on Sept. 20.
Semi-finalists in 2011, Wales are drawn in the toughest of the four groups alongside England and Australia and must now do battle without three first-choice backs after centre Jonathan Davies suffered a serious knee injury in March.
"Wales scrum half Rhys Webb has sustained a significant midfoot injury ruling him out of the forthcoming Rugby World Cup," the Welsh Rugby Union said in a statement.
"Rhys will undergo further examination and assessments on both his foot and knee before further details can be announced."
Webb, who has established himself as the first choice number nine for Wales, was carried off on a stretcher during the first half in Cardiff after his left leg became trapped at the back of a ruck.
The WRU said scrumhalf Mike Phillips and wing Eli Walker had been added to the squad as replacements.
"It is extremely disappointing for both Leigh and Rhys," Wales head coach Warren Gatland said.
"They have worked exceptionally hard to establish themselves on the world stage and to prepare for the tournament and we wish them all the best with their recovery."
Walker made his international debut against Ireland last month while Phillips will head to his third Rugby World Cup.
British and Irish Lion Phillips, 33, was a shock omission when Wales cut their squad but he could yet get the chance to add to his 94 caps, although that is likely to come from the bench with Gatland likely to hand a start to Gareth Davies or Lloyd Williams.
Webb released a statement saying "words can’t describe how I’m feeling."
He said: "Really disappointed to be ruled out of the RWC. I really believe that Wales can go on and create something special.
"I appreciate all the messages. It’s great to have so much support from all around the world but let’s get behind the boys. See you in 2016."
(Reporting by Justin Palmer; editing by Amlan Chakraborty)
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