Scopoletin (6-methoxy-7-hydroxycoumarin) belongs to the family of coumarins with numerous pharmacological benefits. The present study deals with examining the efficacy of Nanoencapsulated polymeric Scopoletin (NEP-Sc) in murine colon cancer model. Male Balb/c mice were supplemented with NEP-Sc (2.5 and 5 mg/kg b.w.) and 5-fluorouracil (25 mg/kg b.w.) for 10 days consecutively post-induction of colon cancer. Colon polyps and morphology were assessed using a macroscopical inspection, and their score establishes the ameliorative effect of NEP-Sc. Body weight, diarrhoea score, and spleen weight were also measured. The antioxidant status of the mucosal levels of glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (LPO) and nitric oxide (NO) were evaluated. The β-catenin and Ki-67 levels were analyzed through immunohistochemistry analysis to assess the inflammatory response. ELISA-based analysis was used to measure IL-4, IL-6, IL-10, TNF-alpha, IFN-gamma, and VEGF levels. All the aforementioned parameters were mitigated in AOM/DSS-triggered colon cancer in mice treated with NEP-Sc. Nanoencapsulated polymeric Scopoletin offered protection against AOM/DSS-induced colon cancer in mice. To sum up, our research findings suggest that NEP-Sc may act as a promising candidate for treating colon-associated cancer.