© 2022 Elsevier Inc.VEGFR-2 is a tyrosine kinase receptor for VEGFs that play a central role in tumor angiogenesis. The inhibition of the tyrosine kinase domain of VEGFR-2 has become an attractive therapeutic strategy in recent years for inhibiting tumor growth. In this study, a series of novel 2-oxoquinoxalinyl-1,2,4-triazoles were designed and synthesized as potential antitumor agents and VEGFR-2 inhibitors. Eight compounds in this series showed high growth inhibition against MCF-7 with GI50 ranging from 1.6 to 8.06 µM compared to staurosporine (GI50 = 8.39 µM) and sorafenib (GI50 = 11.20 µM). In addition, the results of the in vitro tyrosine kinase inhibition of VEGFR-2 revealed that most of the compounds possessed IC50 values in the sub-micromolar range. Compound 6g (IC50 = 0.037 µM) showed more potent VEGFR-2 inhibitory activity than sorafenib (IC50 = 0.045 µM). Furthermore, docking studies of the compounds with tyrosine kinase domain of VEGFR-2 (PDB ID: 4ASD) were performed. According to the results, 6g exhibited hydrogen bonding interactions with Glu885, Asp1046 and Cys919 amino acids in a similar way to sorafenib. Finally, physicochemical predictions of target compounds were examined in silico. The results revealed that all the compounds possessed promising drug-likeness profile.