Background. Oral squamous cell carcinoma (OSCC) is one of the most common head and neck squamous cell tumors. MicroRNAs and DNA methylation, as epigenetic mechanisms, regulate the expression of oncogenes and tumor suppressor genes, contributing to the carcinogenic development. However, the current knowledge on the genetic and epigenetic landscape of OSCC is still limited.Objectives. To assess the transcriptomic impact of microRNAs found to be methylated through Infinium genome-wide methylation profiling of archived OSCC tissues, and to analyze their biological role using gene network analysis.Materials and methods. We used the Infinium array-based methylation assay to assess the genome-wide methylation status at the single-CpG-site level of DNA purified from archived OSCC tissue samples. After quality control, filtering out poorly performing probes and normalization of data, we identified the differentially methylated microRNA loci. We performed a literature-based analysis of OSCC transcriptomic data to identify the predicted target genes for each microRNA, followed by individual network and pathway enrichment analyses.Results. The analysis of Infinium methylation array data revealed 1469 differentially hypomethylated loci, 4 of which were of interest, namely hsa-microRNA-124-3, hsa-microRNA-24-1, hsa-microRNA-769, and hsa-microRNA-4500. Network and pathway enrichment analyses revealed multiple pathways modulated through DNA methylation-microRNA expression axes.Conclusions. We describe the transcriptomic impact of 4 differentially methylated microRNAs in OSCC tissues samples and discuss their role in the pathology of OSCC. These results may contribute to a better understanding of how epigenetic mechanisms such as DNA methylation and microRNAs cooperate to impact the development of OSCC.