In our study, we present an environmentally benign procedure for green synthesis of 4-aryl/hetero aryl benzo[h]quinolin-2-one-3-carbonitrile. The synthesis protocol of quinolone carbonitrile derivatives, including the reaction of tetralone 1 and ethyl cyano acetate with hetero aryl and ammonium acetate under solvent-free conditions, compounds 4a–i, 5, and 6, were obtained and its chemical structure was proved by different spectroscopic methods. The present synthetic approach could effectively produce different quinolone carbonitrile derivatives with high yields in the absence of solvent and in short reaction time, making it a green and sustainable process. All new compounds were screened for cytotoxicity on two kinds of acute lymphoblastic leukemia (ALL) cells, CRL-2898, and MOLT-4, and compared with normal human primary peripheral blood mononuclear cells PCS-800-011 using MTT assay. Compound 4g showed potent cytotoxicity with IC50 value 9.81, 9.81 μM against CRL-2898 and MOLT-4, respectively, without effect on normal cell. The most cytotoxic compounds 4g, 5, and 6 were docked into the active site of myeloid cell leukemia-1(Mcl-1). Compounds 4g and 6 showed strong hydrogen bond interaction with Arg263 through their carbonyl groups, achieving a binding mode similar to that of the native ligand.