Colorectal cancer (CRC) is a substantial global health burden, with treatment outcomes significantly influenced by the interaction between the immune system and the tumor microenvironment. This study aims to investigate the role of peripheral blood immune cell subpopulations, particularly CD8+ CD28+ T cells, in predicting treatment response in metastatic CRC patients receiving bevacizumab combined with chemotherapy. A cohort of 45 CRC patients was analyzed. Flow cytometry was utilized to assess immune cell subpopulations. Higher CD8+ CD28+ T cell counts were associated with better treatment responses, including improved objective response rates. In a murine CRC model, the combination therapy significantly inhibited tumor growth and enhanced immune cell function. These findings highlight the importance of CD8+ CD28+ T cells as potential biomarkers for predicting treatment outcomes in CRC. They also suggest that bevacizumab, when combined with chemotherapy, can modulate immune function and improve clinical efficacy.