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 <b>35m</b> exhibits potent HDAC6 inhibitory activity with an IC<sub>50</sub> value of 0.019 μM. To our surprise, <b>35m</b> establishes significant improvement in the pharmacokinetic property with much higher AUC<sub>0-inf</sub> (10292 ng·h/mL) and oral bioavailability (93.4%) than hydroximic acid-based HDAC6 inhibitors Tubastatin A and ACY-1215. Low-dose <b>35m</b> remarkably decreases LPS-induced IL-1β release both <i>in vitro</i> and <i>in vivo</i> by blocking the activation of NLRP3, indicating that <b>35m</b> can be a potential orally active therapeutic agent for the treatment of NLRP3-related diseases.