Previously, we found that hydrazide can serve as zinc binding groups for selective HDAC6 inhibitors and identified the first hydrazide-based HDAC6 inhibitor, 35m, which exhibited modest isoform selectivity. This study aimed to improve the HDAC6 selectivity of 35m, thereby reducing its side effects. Extensive structure-activity relationship studies revealed that the introduction of fluorine atoms at the 2 and 5 positions of the linker phenyl ring in compound 35m significantly enhanced its HDAC6 selectivity while maintaining its potency. The representative compound 9m demonstrated an IC(50) of 0.021 muM against HDAC6, exhibiting at least 335-fold selectivity over other isoforms, along with favorable pharmacokinetic properties and improved safety profiles. Compound 9m inhibits the activation of NLRP3 inflammasome and significantly alleviates symptoms in multiple NLRP3 inflammasome-related disease models, including acute peritoneal, inflammatory bowel disease, and psoriasis. This study enriches the design strategies for selective HDAC6 inhibitors and provides a lead compound for NLRP3 inflammasome-related diseases.