Non-O1/O139 Vibrio cholerae is increasingly reported in the clinical settings. However, intestinal infections via the consumption of non-O1/O139 V. cholerae-carrying seafood are rarely documented in China. In this study, we reported a case of mild watery diarrhea in a young male, caused by non-O1/O139 V. cholerae in the downstream of Liaohe River. Epidemiological investigation showed that this intestinal infection potentially associated with the raw consumption of mollusc. Prior to this finding, we conducted a 6-month pathogen surveillance of three locations along the Liaohe River and identified three environmental non-O1/O139 V. cholerae strains. To confirm the epidemiological links between clinical and environmental strains, high-resolution genomic typing was employed and revealed that V. cholerae isolated from human stool sample was genomically related to the one found in local mollusc and shared a common ancestor with other environmental strains obtained in the upstream sites of the Liaohe River. This fact suggests that the river is a natural reservoir for non-O1/O139 V. cholerae which poses a potential threat to the public health. In summary, our results deepened the insights on the transmission of non-pandemic V. cholerae strains and underscored the significance of genomic surveillance for drinking water along the river sites.