Abstract: Objective To investigate the clinical efficacy of regorafenib combined with immunotherapy or chemotherapy in the laterline treatment of metastatic colorectal cancer (mCRC). Methods A retrospective analysis was conducted on 63 patients with mCRC admitted to the First Affiliated Hospital of Anhui Medical University from January 2021 to December 2023. They were divided into a control group (n=9), a regorafenib plus immunotherapy group (n = 29), and a regorafenib plus chemotherapy group (n = 25) according to different treatment regimens. The control group received regorafenib monotherapy; the regorafenib plus immunotherapy group received regorafenib plus immune checkpoint inhibitors; the regorafenib plus chemotherapy group received regorafenib combined with chemotherapy. The clinical efficacy, survival, and serum biomarkers were compared among the groups. Results There was no statistically significant difference in the objective response rate and disease control rate among the three groups (P ＞ 0.05). The median progression free survival (mPFS) and median overall survival (mOS) of the regorafenib plus immunotherapy group were 5.63 months and 11.56 months, respectively, which were significantly longer than those of the control group (P ＜ 0.05); The mPFS and mOS of the regorafenib plus chemotherapy group were 4.10 months and 9.10 months, respectively, with no statistically significant difference compared to the control group (P ＞ 0.05). COX regression analysis showed that after treatment, a decrease in lymphocyte absolute value (ALC), increases in neutrophil to lymphocyte ratio (NLR), carcinoembryonic antigen (CEA) and carbohydrate antigen 125 (CA125) were independent risk factors for shortened OS (P ＜ 0.05). Conclusion Regorafenib combined with immunotherapy significantly prolongs the survival of patients with mCRC, whereas regorafenib combined with chemotherapy does not confer a survival benefit. Changes in ALC, NLR, CEA, and CA125 levels before and after treatment may serve as potential serum markers for prognostic assessment.