Aim: Cancer is one of the life-threatening diseases which cause severe pathological conditions, leading to mortality. The exhaustive data on the vital role of medicinal plants in combating cancer and related diseases are available since antediluvian times. Materials and Methods: In this present study, cell viability, morphological changes, and IC50 were evaluated by in vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltertazoliumbromide) assay. Hydro-alcoholic and ethyl acetate extracts of fruits Annona muricata (AM) and aerial parts Euphorbia tirucalli (ET) against lung (A549, H1975) and oral (SCC9, SCC25) were used to investigate the potential antitumor activity. Results: Ethyl-acetate extract of AM and ET showed the highest IC50 value, 89.48 μg/mL and 119.2 μg/mL against lung cancer cell line A-549. Among four study extracts, the IC50 value of hydroalcoholic extract of AM showed 184.3 μg/mL against H1975 cell line. The hydroalcoholic extract of AM and ethyl acetate extract of EA showed the IC50 value of 149.7 μg/mL and 156.2 μg/mL against SCC9 cell line. Hydroalcoholic and ethylacetate extract of ET showed the highest cytotoxic potency against SCC25 139.2 μg/mL and 205.6 μg/mL compared to AM. Further, all the study extracts exhibited decrease in % cell viability in the dose-dependent manner. Conclusion: This comprehensive data obtained from the in vitro study indicate that the extracts that showed toxicity toward cancer cell lines can be considered potential chemotherapeutic agents. The data suggest to further confirm the anticancer potential by conducting in vitro and in vivo studies, so that the study plants may be adopted in the treatment of lung and oral cancer.