Various 3,5-disubstituted-1,2,4-oxadiazoles are smoothly formed via copper-catalyzed cascade annulation of amidines and methylarenes. This tandem oxidation-amination-cyclization transformation represents a straightforward protocol to prepare 1,2,4-oxadiazoles from easily available starting materials, with inexpensive copper catalysts and green oxidants. It has the advantages of atom- and step-economy, good functional group tolerance, as well as operational simplicity.