Naturally occurring compounds are considered the most interesting agents to test for cancer prevention and therapy, due to their anticipated multimodal actions and limited toxicity, these compounds could be developed further as a potential anti-cancer agent, both in conventional and combination therapy. To overcome challenges like slow response with small molecules, combination therapy with natural compounds like plant flavonoid quercetin and synthetic anti-cancer drug RITA could be considered effective for cancer therapy. The current study tested synergistic antiproliferative activity/anticancer activity of natural compound quercetin and p53 activator by cell viability assays in COLO-320 (colon) NCI-H23 (lung) and HeLa (cervical). The results revealed that the combination has enhanced antiproliferative activity than the individual drugs in multiple cancer cell lines. Among the tested cell lines, NCI H23 cell lines showed antiproliferative effect with the drug combination.