A series of novel 2-oxoindolin-3-ylidene thiazole derivatives were designed and synthesized, inspired by the pharmacophoric features of the VEGFR-2 inhibitor sunitinib. These compounds were evaluated for antiproliferative activity against a panel of sixty cancer cell lines at the US National Cancer Institute, identifying derivatives 4b, 4c, 4d, 4l, and 6c as the most potent, with mean growth inhibition percentages of 118.86%, 135.32%, 148.27%, 126.16%, and 78.46%, respectively. Further cytotoxicity assessments against the HepG2 cell line revealed IC50 values ranging from 3.13 to 30.54 μM. These compounds also demonstrated strong VEGFR-2 inhibition, with IC50 values of 0.113, 0.047, 1.549, 0.995, and 0.089 μM, respectively, compared to sunitinib's IC50 of 0.167 μM. Selectivity index analysis indicated high selectivity for HepG2 cells over THLE-2 normal cells (1.80–10.26), suggesting favourable safety profiles compared to sunitinib (1.15). Notably, compound 4c induced G0/G1 phase cell cycle arrest, promoted apoptosis, upregulated caspase-3 and -9 expression, and delayed wound closure by 60.74%. Molecular docking studies confirmed strong binding interactions within the VEGFR-2 active site, while in silico ADME and DFT analyses supported favourable pharmacokinetic properties and reactivity. These findings position compound 4c as a promising lead for the development of anticancer agents.