Hydroxamic acid group is one of the characteristic pharmacophores of histone deacetylase (HDAC) inhibitors. But here, we discovered a series of hydroxamic acid-based microtubule destabilizing agents (MDAs), which were derived from shortening the length of the linker in HDAC6 inhibitor SKLB-23bb. Interestingly, the low nanomolar antiproliferative activity of these MDAs depended on the presence of hydroxamic acid groups, but their inhibitory effects on HDAC were lost. Among them, <b>12b</b> showed favorable metabolism stability, high bioavailability, and potent antitumor activity in multidrug-resistant cell lines and A2780/T xenograft model. More importantly, in the patient-derived xenograft models of triple-negative breast cancer and osimertinib-resistant non-small-cell lung cancer, both 20 mg/kg oral and 10 mg/kg intravenous administration of <b>12b</b> could induce more than 70% tumor inhibition without obvious toxicity. Overall, we discovered that <b>12b</b>, as a novel MDA based on hydroxamic acid, could serve as a potential MDA for further investigation.