O‐Acylamidoxime and 1,2,4‐oxadiazole derivatives were synthesized from adamantanecarbonyl chloride 1 and a diversity of arylamidoximes 2 a‐k. First, O‐acylamidoximes intermediates 3 a‐k were synthesized and subsequent cyclization under microwave irradiation afforded 1,2,4‐oxadiazol derivatives 4 a‐k. Molar Heat of Reaction Calorimetry studies performed from O‐acylamidoximes revealed influence of the substituent groups. A one‐pot two‐step methodology was also developed proving to be a viable protocol. Compounds were characterized by 1H and 13C Nuclear Magnetic Resonance (NMR) Spectroscopy, Elemental Analysis or High Resolution Mass Spectral Analysis, and subjected to cytotoxic studies in non‐tumoral Vero cells and antiproliferative activity tests in six malignant cell lines. Our findings suggest that compounds 3 derivatives presented a concentration‐dependent profile for chronic myeloid leukemia (K562) and acute promyelocytic leukemia (HL‐60) cell.