Zinc-dependent histone deacetylases (HDACs) play critical roles in numerous (patho)physiological processes and thus serve as targets of therapeutic interventions in cancers and neurological diseases. HDAC inhibitors used in clinic typically contain a hydroxamate zinc-binding group (ZBG) yet the use of alternative ZBGs, including heterocyclic oxadiazoles, can confer to higher isoenzyme selectivity and more favorable pharmacological profiles. We co-crystallized HDAC6 and an oxadiazole-based inhibitor to shed light onto inhibitor recognition by the enzyme. Surprisingly, the crystal structure of the HDAC6/inhibitor complex revealed unexpected oxadiazole ring hydrolysis converting the parent oxadiazole into an acylhydrazide that chelates the active-site zinc ion of the enzyme. An identical cleavage pattern was also observed in vitro using the purified HDAC6 and QM/MM calculations corroborated kinetic in-solution experiments and provided the detailed reaction scheme of the hydrolysis, including structures of all intermediates and corresponding energy barriers. Overall, our data provide evidence that oxadiazole warheads can be efficiently transformed in active sites of target metallohydrolases into compounds with distinct selectivity and inhibition profiles.