Via an imine-protection strategy, we herein present an unprecedented copper-catalyzed oxidative multicomponent annulation reaction for direct synthesis of quinazolinones. The construction of various products is achieved via formation of three C-N and one C-C bonds in conjunction with the benzylic functionalization. The merits of easily available feedstocks, naturally abundant catalyst, good functional group and substrate compatibility, and release of H2O as the byproduct make the developed chemistry a practical way to access quinazolinones.