In anticancer drug discovery, multi-targeting compounds have been beneficial due to their advantages over single-targeting compounds. For instance, VEGFR-2 has a crucial role in angiogenesis and cancer management, whereas HDACs are well-known regulators of epigenetics and have been known to contribute significantly to angiogenesis and carcinogenesis. Herein, we have reported nineteen novel VEGFR-2 and HDAC dual-targeting analogs containing diaryl-pyrazoline thiazolidinediones and their <i>in vitro</i> and <i>in vivo</i> biological evaluation. In particular, the most promising compound <b>14c</b> has emerged as a dual inhibitor of VEGFR-2 and HDAC. It demonstrated anti-angiogenic activity by inhibiting <i>in vitro</i> HUVEC proliferation, migration, and tube formation. Moreover, an <i>in vivo</i> CAM assay showed that <b>14c</b> repressed new capillary formation in CAMs. In particular, <b>14c</b> exhibited cytotoxicity potential on different cancer cell lines such as MCF-7, K562, A549, and HT-29. Additionally, <b>14c</b> demonstrated significant potency and selectivity against HDAC4 in the sub-micromolar range. To materialize the hypothesis, we also performed molecular docking on the crystal structures of both VEGFR-2 (PDB ID: 1YWN) and HDAC4 (PDB-ID: 4CBY), which corroborated the designing and biological activity. The results indicated that compound <b>14c</b> could be a potential lead to develop more optimized multi-target analogs with enhanced potency and selectivity.