BACKGROUND Immune checkpoint inhibitors have demonstrated significant efficacy in colorectal cancer (CRC) patients with microsatellite instability-high or deficient mismatch repair. However, their efficacy as monotherapy is limited in microsatellite stable/proficient mismatch repair (MSS/pMMR) subtypes. AIM To provide an evidence-based rationale for optimizing later-line therapeutic strategies in advanced MSS/pMMR CRC. METHODS This study conducted a systematic retrospective analysis to evaluate the efficacy and safety of a triple-combination regimen comprising programmed death 1 inhibitors, fruquintinib and docetaxel administered as third-line therapy in 13 patients with advanced MSS/pMMR CRC. RESULTS Primary endpoints included progression-free survival and disease control rate. Intention-to-treat analysis showed median progression-free survival 7.0 months, median overall survival 18.5 months, disease control rate 61.5%, with manageable toxicity. CONCLUSION Although this is a small-sample retrospective study, it preliminarily validates the synergistic effect of programmed death 1 inhibitors combined with fruquintinib and docetaxel in MSS/pMMR CRC, providing a novel strategy with translational significance for later-line treatment in advanced patients.