Background: The immune microenvironment of deficient mismatch repair or microsatellite instability high (dMMR/MSI-H) colorectal cancer exhibits better immune activity, and patients with dMMR/MSI-H colorectal cancer benefit from immunotherapy with programmed death-1 (PD-1)/PD-1 ligand (PD-L1) inhibitors and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibitors as a first-line treatment. However, for microsatellite-stable (MSS) colorectal cancer, which accounts for the majority of the cases of colorectal cancer, immunotherapy has yielded little success, especially in cases of patients with advanced colorectal cancer in whom multiple lines of chemotherapy have failed. Hence, safe and effective targeted treatment strategies are urgently needed to achieve greater survival benefits. Case Description: We report a case in which next-generation sequencing (NGS) and immunohistochemistry (IHC) showed that that the patient's molecular characteristics were as follows: MSS, low expression of PD-L1, and high tumor mutation burden (TMB-H). Due to the failure of multiple lines of chemotherapy and severe chemotherapeutic adverse effects, a combined targeted immunotherapy regimen was utilized. After 6 months of treatment, imaging suggested near-complete clinical remission, and at the 18-month follow-up, the patient had a good quality of life and imaging showed no tumor recurrence. Conclusions: This case suggests that a good response to a combined targeted immunotherapy regimen can be achieved in patients with MSS metastatic colorectal cancer, in addition, it also suggests that TMB-H is a predictive biomarker for clinical benefit from immunotherapy in MSS metastatic colorectal cancer.