Objective To investigate the clinical efficacy and safety of Jianpi Jiedu Tongluo Prescription combined with regorafenib in the laterline treatment of metastatic colorectal cancer (mCRC). Methods A retrospective cohort study was conducted among 140 mCRC patients, who were divided into control group (regorafenib monotherapy) and observation group (Jianpi Jiedu Tongluo Prescription combined with regorafenib), with 70 patients in each group. The primary endpoint was overall survival (OS), while the secondary endpoints included progressionfree survival (PFS), objective response rate (ORR), disease control rate (DCR), and the incidence rate of adverse events. Response Evaluation Criteria in Solid Tumors version 1.1 was used to evaluate treatment outcome, the KaplanMeier method was used for survival analysis, and the Cox regression model was used to investigate prognostic factors. Results The observation group had a median OS of 10.7 months \[95% confidence interval (CI): 9.0212.38\] and a median PFS of 6.6 months (95% CI: 4.888.32), while the control group had a median OS of 8.6 months (95% CI: 7.909.30) and a median PFS of 3.6 months (95% CI: 2.654.55), and there were significant differences in median OS and PFS between the two groups (P<0.05). There was no significant difference in ORR between the observation group and the control group (7.14% vs 2.86%, P>0.05), while there was a significant difference in DCR between the observation group and the control group (68.57% vs 45.71%, P<0.05). Compared with the control group, the observation group had significantly lower incidence rates of adverse events such as handfoot skin reaction, abdominal pain, and diarrhea (P<0.05). The Cox regression analysis showed that ECOG score, the presence or absence of liver metastasis, and treatment modality were independent prognostic factors in patients with mCRC. Conclusion The combination of Jianpi Jiedu Tongluo Prescription and regorafenib can significantly prolong both OS and PFS in mCRC patients, reduce the incidence rates of regorafenibrelated adverse events, and improve the quality of life of patients.