Colorectal cancer (CRC) is the world’s third most deadly disease, it is very urgent to discover new diagnostic biomarker and therapeutic targets. Interleukin-36α (IL-36α) is a proinflammatory factor, which can initiate the inflammatory response and especially raise the overall systemic Th1 immune response. In the present study, we clarified the new role of IL-36α in colorectal cancer. we observed that IL-36α is down-regulated in human colorectal cancer tissues and colorectal cancer patients with high IL-36α expression had a better prognosis. Then, we constructed IL-36α overexpressing cell lines CT26-IL-36α and HT29-IL-36α to verify the effect of IL-36α on tumor cells. Results showed that IL-36α over-expression could directly inhibit the proliferation, the migration and invasion of tumor cells. We then established CT26 and CT26-IL-36α tumor xenograft model and lung metastasis model to determine the effect of IL-36α in vivo. Results showed that IL-36α overexpression could significantly inhibit the growth and lung metastasis of tumors, and enhance the infiltration and cytokine secretion of CD8+ T lymphocyte cells. Then, we found that CT26-IL-36α secrete more CXCL10 and CXCL11 to enhance the infiltration of CD8+ T lymphocyte than that of CT26-vector cells. These results suggested that IL-36α could serve as a promising therapeutic target for colorectal cancer through directly inhibiting the ability of tumor cells and enhancing the infiltration and function of CD8+ T lymphocytes.