Objective: To investigate the clinical efficacy of combining Xuejie Powder with regorafenib as a third-line therapy for metastatic colorectal cancer (mCRC). Methods: Between January 2023 and January 2025, a study was conducted involving 60 mCRC patients at Guangxin District Hospital of Traditional Chinese Medicine and Jiangxi University of Traditional Chinese Medicine Affiliated Hospital. These patients were randomly assigned to two groups: a control group ( treated with regorafenib, n = 30 ) and an observation group ( treated with Xuejie Powder combined with regorafenib, n = 30 ).The clinical efficacy, serum tumor markers before and after treatment? [ carbohydrate antigen 242 ( CA242 ), carcinoembryonic antigen ( CEA ), carbohydrate antigen 50 ( CA50 ) and carbohydrate antigen 19-9 ( CA19-9 ) ] and adverse reactions after treatment were compared between the two groups. Results: After treatment, the objective remission rate and disease control rate of the observation group were higher than those of the control group ( P < 0.05 ). Post-treatment, CA19-9, CA50, CEA, and CA242 levels declined in both groups, with the observation group demonstrating consistently lower values than the control group (P<0.05). Additionally, no significant difference in adverse reaction rates was observed between the two groups during treatment (P>0.05). Conclusion: Xuejie Powder combined with regorafenib is effective in the third-line treatment of mCRC, which can effectively regulate the level of serum tumor markers and has good safety.