We found aberrant overexpression of NSUN2 in ESCCs, which was highly associated with poor prognosis and advanced tumor stages, suggesting a prognostic value for NSUN2. In-vitro experiments showed that NSUN2 promoted malignant phenotypes of ESCC cells dependent on its methyltransferase activity, suggesting an m5C-dependent oncogenic role of NSUN2. In according with in-vitro data, NSUN2 silencing markedly suppressed ESCC tumor initiation and progression in the 4-NQO-induced ESCC model in transgenic mice, indicating that NSUN2 overexpression may be an early molecular event of ESCC. Here, NSUN2 is linked to esophageal squamous cell carcinoma.