BACKGROUND: Colorectal Cancer (CRC) is widely prevalent worldwide and its incidence is increasing. Chemotherapy is an important treatment method for colorectal cancer in addition to surgery, but it often causes physical and mental pain to patients due to its side effects. TCM emphasizes evidence-based treatment and a holistic concept, and the combination of TCM and chemotherapy can reduce chemotherapy side effects, improve chemotherapy efficacy, and enhance patients' immunity. Yiqi Jianpi Kangai Decoction (YQJP) has been used clinically to treat patients with advanced colorectal cancer and may improve their immune function and prognosis. However, its mechanism has not been elucidated. OBJECTIVE: The study aims to explore the effect and mechanism of YQJP on enhancing the therapeutic effect of chemotherapy on spleen qi deficiency type CRC mice. METHODS: We used HPLC/MS to characterize the active substance components in YQJP. We established the spleen qi deficiency model induced by using the compound methods of diarrhea of bitter and cold, starvation, and full and excessive labor. and then inoculated CT-26 mouse colon cancer cells subcutaneously to establish the CRC Mice. We also evaluated the efficacy and mechanism of YQJP by using oral Yiqi Jianpi Kangai Decoction combined with an intraperitoneal injection of chemotherapeutic drugs (FOLFOX regimen). We evaluated the efficacy and safety of YQJP by observing the general condition (body weight, tumor size, food intake, hair condition, stool condition), HE staining, blood routine, and organ index of the mice. The expression of CD8 RESULTS: YQJP contains 7 herbal compounds, which can effectively improve body weight, spleen condition, and bone marrow suppression in tumor-bearing mice inhibit tumor growth, and do not damage tissues and organs, which initially confirmed the anti-cancer effect and safety of YQJP. Further experiments showed that YQJP could elevate the proportion of CD8 CONCLUSION: The combination of YQJP with chemotherapy had the effect of tumor suppression and enhanced chemotherapeutic efficacy in the spleen qi deficiency CRC mice. The related mechanism may be related to inhibiting proliferation, promoting apoptosis of tumor cells, increasing Th17 cells in tumor tissues, and decreasing Treg cell expression to improve the tumor microenvironment.