The relationship between oral squamous cell carcinoma (OSCC) and Corneodesmosin (CDSN) remains unclear. This study aims to explore the correlation between CDSN and the prognosis and survival time of patients with OSCC.Bioinformatics were used to identify the hub role of CDSN in the OSCC. A total of 200 patients with OSCC were recruited. Clinical and follow-up data were recorded, and the expression level of CDSN was detected. Pearson chi-square test and Spearman correlation coefficient were used to analyze the relationship between prognosis and related parameters in patients with OSCC. Univariate and multivariate Logistic regression and Cox proportional risk regression were applied for further analysis, and receiver operating characteristic curve and survival curve of subjects were plotted.CDSN was identified as the most significant hub gene of the OSCC by the cytoHubba. By the comparative toxicogenomics database (CTD) analysis, there was strong relationship between the CDSN and mouth neoplasms, head and neck neoplasms, squamous cell carcinoma of head and neck. The OSCC patients with low expression level of CDSN have poor overall survival compared with the high expression level of CDSN (HR = 0.75, 95% confidence interval [95%CI]: 0.57-0.98, P = .036). Spearman correlation coefficient analysis showed that CDSN expression level was significantly correlated with prognosis (ρ = -0.528, P < .001). Multivariate Logistic regression analysis showed that poor prognosis (odds ratio [OR] = 0.096, 95%CI: 0.049-0.189, P < .001) was significantly associated with low expression of CDSN. Cox regression analysis showed that the survival time of OSCC patients was shorter when CDSN expression was low (HR = 0.588, 95%CI: 0.420-0.823, P = .002). Strong predictive value of CDSN for the OSCC survival time was obtained by the biological process (BP)-neural network and support vector machine (SVM).CDSN was significantly correlated with OSCC, and the shorter the survival time of patients with OSCC was, the worse the prognosis was.Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.