Cancer is the leading cause of death worldwide, with breast and colorectal cancers being the two most common cancer forms.The present work was designed to investigate the probable oncolytic effect of lentogenic and velogenic Newcastle disease viruses on MCF-7 and Caco-2 cell lines compared to the commonly used chemotherapies as an in vitro preliminary study to further prelude an in vivo study.The cytotoxic effects ofNewcastle disease virus strains NDV/chicken/Egypt/Giza/2015 (velogenic NDV genotype VIID) and Lasota strains, as well as the commonly used chemotherapies (Paclitaxel or Doxorubicin) were investigated on MCF-7 and Caco-2 cell lines at different concentrations. Both the human colorectal adenocarcinoma (Caco-2) and the Michigan Cancer Foundation-7 (MCF-7) human breast cancer cell lines were inoculated with NDV VIID and LaSota at concentrations of 10^-2, 10^-3, 10^-4, and 10^-5, Paclitaxel (for MCF-7) at concentrations of 0.5, 1, and 2 μM, and Doxorubicin (for Caco-2) at 0.1, 1 and 10 μM in four replicates each. The cytotoxic effect was performed using a neutral red assay for both virus strains and in combination with chemotherapeutic agents. The present study clarified that both VIID and LaSota strains of NDV, particularly at titers of 10^-3 and 10^-4 TCID50/ml, respectively, displayed a significant (P ≤ 0.05) cytotoxic effect on both MCF-7 and Caco-2 cell lines. Moreover, the combined treatment of the TCID50 (Tissue Culture Infective Dose 50) doses of both NDV strains and the tested chemotherapies showed a more significant (P ≤ 0.05) cytotoxic effect than the sole use of each. Depending on the results, we can conclude that this study opens the way for further in vivo studies aiming to provide more safe treatment for human cancers, save human lives, and avoid dramatic ends.