Novel dual HDAC3/tubulin inhibitors were designed and efficiently synthesized by combining the pharmacophores of SMART (tubulin inhibitor) and MS-275 (HDAC inhibitor), among which compound <b>15c</b> was found to be the most potent and balanced HDAC3/tubulin dual inhibitor with high HDAC3 activity (IC<sub>50</sub> = 30 nM) and selectivity (SI > 1000) as well as excellent antiproliferative potency against various cancer cell lines, including an HDAC-resistant gastric cancer cell line (YCC3/7) with IC<sub>50</sub> values in the range of 30-144 nM. Compound <b>15c</b> inhibited B16-F10 cancer cell migration and colony formation. In addition, <b>15c</b> demonstrated significant <i>in vivo</i> antitumor efficacy in a B16-F10 melanoma tumor model with a better TGI (70.00%, 10 mg/kg) than that of the combination of MS-275 and SMART. Finally, <b>15c</b> presented a safe cardiotoxicity profile and did not cause nephro-/hepatotoxicity. Collectively, this work shows that compound <b>15c</b> represents a novel tubulin/HDAC3 dual-targeting agent deserving further investigation as a potential anticancer agent.