β-carboline derivatives have been reported to possess multi-therapeutic potential owing to the manifestations of different pharmacological effects. In the current study, L-tryptophan was utilized as a starting material for the efficiently synthesis of several hybrid compounds of the type β-carboline N2-fused imidazole using aromatization, oxidation and decarboxylation reaction. The target products were obtained in good yields and were characterized by NMR (1H and 13C) and HRMS analysis. The newly synthesized β-carboline N2-fused imidazole derivatives were evaluated for their cytotoxic activity against five cancer cells, namely, MCF-7, A-549, BGC-823, CT-26, and Bel-7402 using viability testing tetrazolium dye (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) (MTT). The results showed that most of the compounds exhibited moderate to excellent activity against the tested cancer cell lines. Especially compound 3-benzyl-11-(3-phenylpropyl)-11H-imidazo[1",5":1,2]pyrido[3,4-b]indole (Ⅴr), bearing a benzyl group in imidazole ring and a 3-phenylpropyl in β-carboline core, was found to be the most potent anti-proliferative agent against CT-26, Bel-7402, and MCF-7 cell lines with the IC50 values lower than 10 μmol/L. In molecular docking studies, blind docking of compounds 3-benzyl-11-methyl-11H-imidazo [1",5":1,2]pyrido[3,4-b]indole (Ⅴa), 3-benzyl-11-butyl-11H-imidazo[1",5":1,2]pyrido[3,4-b]indole (Ⅴf), and 3-benzyl-11-(3-phenylpropyl)-11H-imidazo[1",5":1,2]pyrido[3,4-b]indole (Ⅴr) were accomplished to find the interactions between the compounds and VEGFR2 enzyme.