Background: colorectal cancer is considered to be the third most common cause of deaths in both men and women. The incidence of colorectal cancer cases has been rising at an alarming rate. In most cases, colon cancer treatment involves chemotherapy. However, toxicity and tumor cell drug resistance are outstanding obstacles to this treatment. Scientific studies suggested that combining certain chemotherapy treatments with specific antioxidants at defined dosages can improve drug efficacy or may reduce side effects severity.5-Fluorouracil, which is used in the treatment of breast, stomach and pancreatic cancer, remains the cornerstone of CRC treatment, although widely used in combination with several other drugs. Many effective drugs, including those actually used for cancer treatment, have been developed from botanical sources. Resveratrol is a pleiotropic phytochemical which is belong to the stilbene family. Although, it is only significantly present in grape products. Many preclinical studies investigated its anticancer properties in a plethora of cellular and animal models. Aim of the work: in the present study, the anticancer effects of Resveratrol alone or combined with 5-Fu were assessed on experimentally induced colorectal cancer in rats. Results: the results of this study indicated that RES had a better therapeutic effect against N-methylnitrosourea induced colorectal cancer than 5-Fu alone and when in combination with each other they diminished the cytotoxic effect of 5-Fu and enhanced normal histological appearance of colon tissue, which could be a promising alternative for resistant colorectal cancer.  However, the exact mechanisms involved needs to be further explored. Conclusion: our results suggested that both natural compounds could be in the future a possible alternative to enhance the efficiency of 5-Fu in resistant colon cancer cells. This study supports the potential of plant extracts as source of bioactive compounds with biomedical applications.