A novel series of 2-phenylbenzimidazole scaffold was designed as dual tyrosine kinase inhibitors based on targeted chemotherapy. All compounds were assessed for their antiproliferative activity against 60 NCI-cancer cell lines, where four compounds 14, 15, 17, and 18 showed superb growth inhibition values, and meanwhile proved safe towards WI-38 normal cells (IC50 range of 39.14–86.66 µM) compared to Doxorubicin (IC50= 6.72 µM). Hence, they were further in vitro evaluated for dual inhibition of Aurora A and CDK-6 enzymes after kinase selectivity profiling, using an extensive docking study to filter off-target enzymes. The four compounds displayed dual enzymatic inhibition, with compounds 14 and 18 being even more potent regarding CDK-6 with IC50 values of 0.197 µM and 0.172 µM, respectively, than Staurosporine (IC50=0.319 µM), and highly potent towards Aurora A, with IC50 values of 74 nM and 62 nM, respectively, compared to 47 nM for Danusertib. Compounds 14, 15, 17, and 18 triggered cell cycle arrest at the G1 phase and induced total apoptosis of HCT-15 cells by 30.96 % - 45.63 %. In Silico studies including molecular docking, physicochemical properties, compliance with Lipinski's rule, and radar plot technique were applied and were found to be in good agreement with the biological results.