The Roma ace suffered a calf injury in the shock 1-0 defeat to Costa Rica on Friday, and the nation's medical staff revealed that De Rossi will not face the South Americans.
"It is very likely De Rossi won't be able to play against Uruguay," professor Enrico Castellacci told reporters.
"There are no lesions to the soleus muscle. It simply is an injury that requires a few days to recover from.
"He felt this pain during the second half and it intensified towards the end of the game. The tests showed bruising on the calf muscle that will very likely stop him from playing against Uruguay."
Cesare Prandelli's side need only a draw against the Uruguayans in order to progress into the last 16.