In the current study, a new series of 5-nitrobenzimidazole-pyrimidine hybrids 12a,b, 13 and 14a-c were designed as VEGFR-2 inhibitors targeting hepatocellular carcinoma. The designed and synthesized conjugates demonstrated a moderate to potent inhibitory activity on VEGFR-2 with IC50 reaching 2.83 µM. Moreover, they demonstrated a moderate to potent cytotoxic activity on HepG2 cell line. Compound 14c was the most potent hybrid with IC50 of 2.83 µM on VEGFR-2 and IC50 of 4.37 µM on HepG2 cell line. In silico docking of the synthesized hybrids 12a,b, 13 and 14a-c in the VEGFR-2 binding pocket proved their capability to perform the important interactions required for VEGFR-2 inhibition at its binding site. In addition, the synthesized molecules proved promising predicted ADME properties to be further optimized for the discovery of new targeted anticancer agents.