The Commission said the restructuring of the four banks "will allow them to become viable in the long-term without continued state support".
Banco de Valencia, whose independent future could not be secured, will be sold and integrated into CaixaBank, the Commission said in a statement.
Spain secured funding of up to 100 billion euros from its eurozone partners in June to help rescue its banks. "The approval ... is a milestone in the implementation of the (accord) ...," European Competition commissioner Joaquin Almunia said.