Introduction: MicroRNAs (miRs) are a group of endogenous, non-coding, 18-24 nucleotide length single-strand RNAs that mediate gene expression at the post-transcriptional level through mRNA degradation or translational repression. They are involved in regulating diverse cellular biological processes such as cell cycle, differentiation, and apoptosis. The deregulation of miRs affects normal biological processes, leading to malignancies, including oral squamous cell carcinoma (OSCC). This study evaluates the expression level of miR-21-5p and miR-429 genes in biopsy samples from patients with OSCC and performs a comparison with controls. Materials and Methods: In this study, tissue samples were obtained from 40 individuals (20 OSCC patients and 20 healthy controls) to determine miR-21-5p and miR-429 expression using the ΔCT method and analyzed by the Mann–Whitney test. Results: The mean age of subjects in the control and patient groups was 47.15 and 53.8 years, respectively. According to the Mann–Whitney test, significant differences were observed in miR-21-5p (p p = 0.0191) expression levels between the two groups (p < 0.05). Conclusions: The expression of miR-21-5p, miR-429, and combined miRNAs in the OSCC group was significantly higher compared to the control group. As a result, changes in the expression of these biomarkers in cancerous tissues could potentially be considered as a marker for the early diagnosis of OSCC.