Objective To analyze the expression of SEC61G in oral squamous cell carcinoma (OSCC) tissues and cell lines and determine its correlations with the clinicopathological features and prognosis of patients with OSCC. Methods The expression of SEC61G in OSCC tissues and its diagnostic and prognostic value were detected in the TCGA database. The expression levels of SEC61G in paraffin-embedded OSCC tissues and adjacent normal tissue specimens of 64 patients with OSCC were detected by immunohistochemistry. The correlation of SEC61G expression in OSCC tissues with the clinicopathological features was analyzed. Kaplan-Meier survival curve analysis showed that the expression of SEC61G correlated with the overall survival time of patients with OSCC. Cox regression analysis was used to analyze prognostic influence factors. Results The expression of SEC61G in OSCC tissues was significantly higher than that in para-carcinoma tissues (P < 0.05), consistent with the results of the TCGA database analysis, and its expression was closely related to N stage and clinical stage (P < 0.05). The overall survival of patients with OSCC in the group with low SEC61G expression was significantly higher than that in the high SEC61G expression group (P < 0.05). N stage and SEC61G expression were the prognostic influence factors for patients with OSCC (P < 0.05). SEC61G expression was an independent predictor of the prognosis of patients with OSCC (P < 0.05, AUC=0.923). Conclusion SEC61G is highly expressed in OSCC tissues and associated with N stage and clinical stage. Its high expression is associated with poor prognosis of patients. It may be a diagnostic biomarker for OSCC.