Cancer is a major public health problem in all countries and remains as one of the top leading causes of death worldwide. Herein we report the synthesis of novel series of triazoloquinazolines as potential anticancer agents. Structures of this set of compounds were confirmed by different spectral data including IR, ¹H NMR, ¹³C NMR, Mass spectra, and elemental analyses. All the newly synthesized compounds were evaluated for their anti-proliferative activity against four human cancer cell lines namely; Hepatocellular carcinoma (HePG-2), Mammary gland breast cancer (MCF-7), Human prostate cancer (PC3) and Colorectal carcinoma (HCT-116)). Results of cytotoxicity evaluation showed that the synthesized compounds displayed moderate cytotoxic activity against the selected cancer cell lines. Compound 9 showed the highest anti-proliferative effect followed by compound 7 against colorectal carcinoma cell line (HCT-116) with IC₅₀ values of 17.35 and 27.05 µM respectively. As well, both compounds showed moderate activity against hepatocellular carcinoma (HePG2) with IC₅₀ values of 29.47 and 39.41 µM respectively.