Background:: Colon cancer is responsible for increasing death rate worldwide. Commonly used anticancer drugs have various side effects and their clinical usage must be limited due to their toxicity. Objective:: The present research aimed to evaluate the anticancer potential of Lepidium sativum L. (LS) seeds aqueous extract against azoxymethane/dextran sodium sulfate (AOM/DSS) induced-colon cancer in male albino mice. Methods:: Low (200 mg/kg) and high (400 mg/kg) doses of LS seeds extract were used in treatment of induced colon cancer in different grades. Results:: The present results report that LS treatment for colon cancer mice, especially the high dose, decreases colon polyps/tumor incidence and size, tissues disorder, expression of P53 and increases apoptosis in colon tissue. Moreover, LS decreases micronucleus induction in polychromatic (PCE), increases PCE/normochromatic erythrocytes ratio and decreases the percentage of sperm abnormalities. Conclusion:: The present study reports LS anticancer potential for induced colorectal cancer mice by ameliorating the inflammatory steps of colon.