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This study tried to assess the prognostic value of semaphorin (SEMA) family genes in patients with tongue squamous cell carcinoma (TSCC) and the potential epigenetic alterations of the genes. The part of third-level TSCC data in The Cancer Genome Atlas-Head and Neck Squamous Cell Carcinoma (TCGA-HNSC) was extracted using the UCSC Xena browser for analysis. Among 20 SEMA genes examined, 7 were markedly upregulated, while 8 were substantially decreased in TSCC tissues compared with adjacent normal tissues. SEMA3A was the only gene with independent prognostic value in terms of recurrence-free survival (RFS) in multivariate analysis (hazard ratio [HR]: 1.697, 95% CI: 1.228–2.345, p = 0.001). Among the individual exons of SEMA3A, the exon 9 had a better prognostic value in terms of recurrence than total SEMA3A expression and its expression also independently predicted shorter RFS (HR: 2.193, 95% CI: 1.463–3.290, p < 0.001). The methylation levels of two CpG sites (cg06144675 and cg13988052) were moderately correlated with SEMA3A expression. Interestingly, cg06144675, which locates at the promoter region, showed a negative correlation with SEMA3A expression, whereas cg13988052, which is in the intron of SEMA3A gene body showed a positive correlation with SEMA3A expression. In conclusion, SEMA3A expression is aberrantly upregulated in TSCC tissues. Its exon 9 expression is a potentially valuable prognostic marker of unfavorable RFS in TSCC patients. Both promoter hypomethylation and gene body hypermethylation might contribute to the dysregulation. [ABSTRACT FROM AUTHOR]