DNA methyl transferase 3A (DNMT3A) is an enzyme acting by adding a new methyl group to DNA favoring DNA silencing and carcinogenesis. Cytokines were said to assist epigenetic switch and enhance the activation of methyltransferases in many cancer types. The role of chemokine (C-X-C motif) ligand 1 (CXCL1) in cancer development was proved in many reports. In this study, we suggested that CXCL1 might induce activation of DNMT3A, affecting carcinogenesis of oral squamous cell carcinoma (OSCC). Immunohistochemical (IHC) scoring was calculated and statistical correlation was performed to evaluate the expression of epithelial DNMT3A in addition to epithelial and mesenchymal CXCL1 in OSCC and normal mucosal samples. DNMT3A, epithelial, and mesenchymal CXCL1 revealed a statistically significant increase in immune scoring from normal mucosa and between different tumor grades, besides a significant relation of the expressions with tumor size, stage, and lymph node involvement. Pearson’s correlation detected a statistically significant correlation of DNMT3A with epithelial and mesenchymal CXCL1. Thus, CXCL1 overexpression may be associated with DNMT3A upregulation. DNMT3A, epithelial, and mesenchymal CXCL1 were associated with histological grades and advanced tumor characters suggesting them as reliable prognostic biomarkers in patients of OSCC.