In this study, we report the first highly selective HDAC6 inhibitor with hydrazide as the zinc-binding group (ZBG), which displays superior pharmacokinetic properties to the current hydroxamic acid inhibitors. Structure-activity relationship study reveals that ethyl group substituent hydrazide-based ZBG and cap group with more substantial rigidity and larger volume increase the HDAC6 selectivity of designed compounds. Representative inhibitor 35m exhibits potent HDAC6 inhibitory activity with an IC50 value of 0.019 μM. To our surprise, 35m establishes significant improvement in the pharmacokinetic property with much higher AUC0-inf (10292 ng·h/mL) and oral bioavailability (93.4%) than hydroximic acid-based HDAC6 inhibitors Tubastatin A and ACY-1215. Low-dose 35m remarkably decreases LPS-induced IL-1β release both in vitro and in vivo by blocking the activation of NLRP3, indicating that 35m can be a potential orally active therapeutic agent for the treatment of NLRP3-related diseases.