Development of synthetic procedures for the preparation of 1,3,4-oxadiazole derivatives has always been in the interest of researchers as a result of their widespread biological activities. In this study, an ultrasound-assisted procedure was proposed for the synthesis of 1,3,4-oxadiazol-2-amines form the reaction of hydrazides and cyanogen bromide. They were efficiently produced in 81–93% yields in the presence of ethanol and potassium bicarbonate as the reaction media and the base, respectively. Their antioxidant properties were determined via DPPH free radical scavenging method as one of the most basic steps in identifying other related biological effects. IC50 values were in the range of from 0.237 to 0.863 mM. The synthesized 1,3,4-oxadiazoles are protective agents against oxidative stress, and can be used in the treatment of cancer, candidiasis, diabetes, neurodegenerative and inflammatory diseases. Furthermore, bond dissociation energies (BDEs) and electron densities based NCI (non-covalent interactions) were calculated using density-functional theory (DFT) to understand the observed reactivities. It was found that reversible dipole-dipole forces play a key role in most interactions.