Objective To evaluate the clinical significance of plasma exosomal vacuolar protein sorting-associated protein 37C (VPS37C) combined with serum tumor markers carbohydrate antigen 125 (CA125) and alkaline phosphatase (ALP) in distinguishing patients with metastatic colorectal cancer (mCRC) or non-metastatic colorectal cancer (nmCRC). Methods A total of 85 patients who were diagnosed with colorectal cancer through pathology and imaging in Shuguang Hospital, Shanghai University of Traditional Chinese Medicine from Dec. 2020 to Sep. 2022 were selected, including 46 patients with nmCRC and 39 with mCRC. Another 17 volunteers who underwent physical examination in Shuguang Hospital, Shanghai University of Traditional Chinese Medicine during the same period were selected as healthy controls. The exosomes isolated from circulating plasma were identified by transmission electron microscopy and Western blotting. The levels of plasma exosomal VPS37C, serum CA125 and ALP were detected, and the clinical diagnostic efficacies of these 3 indicators alone or in combination for mCRC were analyzed using receiver operating characteristic curves. Results The levels of plasma exosomal VPS37C, serum CA125 and ALP were increased in the mCRC patients (P＜0.05, P＜0.01). The expression of the 3 indicators in colorectal cancer TNM stage Ⅳ patients was higher than that in TNM stage 0-Ⅲ patients (P＜0.05, P＜0.01). The diagnostic efficacy of the combination of the 2 or 3 indicators for mCRC was higher than that of any single indicator. The combination of the 3 indicators had the best diagnostic efficacy, with a specificity of 90.91%, an accuracy of 78.69%, and an area under curve of 0.813 9 (95% confidence interval 0.697 0-0.930 7, P＜0.000 1). Conclusion Circulating plasma exosomal VPS37C may be a valuable diagnostic marker for mCRC, and its combination with serum CA125 and ALP has better clinical diagnostic value.