Most vascular disrupting agents (VDAs) fail to prevent the regrowth of blood vessels at the edge of tumors, causing tumor rebound and relapse. Herein, a series of novel multifunctional vascular disrupting agents (VDAs) capable of inhibiting microtubule polymerization and histone deacetylases (HDACs) were designed and synthesized using the tubulin polymerization inhibitor <b>TH-0</b> as the lead compound. Among them, compound <b>TH-6</b> exhibited the most potent antiproliferative activity (IC<sub>50</sub> = 18-30 nM) against a panel of cancer cell lines. As expected, <b>TH-6</b> inhibited tubulin assembly and increased the acetylation level of HDAC substrate proteins in HepG2 cells. Further <i>in vivo</i> antitumor assay displayed that <b>TH-6</b> effectively inhibited tumor growth with no apparent toxicity. More importantly, <b>TH-6</b> disrupted both the internal and peripheral tumor vasculatures, which contributed to the persistent tumor inhibitory effects after drug withdrawal. Altogether, <b>TH-6</b> deserves to be further investigated for the new approach to clinical cancer therapy.