Background: Oral squamous cell carcinoma (OSCC) is the most prevalent cancer among the Head and Neck Squamous cell carcinomas (HNSCC) group. Most OSCC cases are diagnosed at advanced stages, resulting in poor survival and a high mortality rate. This study aimed to investigate the changes in expression levels of miR-589-5p, miR-569, and c-Fos (as a target gene) in tumor and adjacent normal tissues from OSCC patients. Also, the association between the c-Fos gene expression and several clinicopathological factors was evaluated. Methods: c-Fos was predicted as a potential target gene of miR-589-5p and miR-569 using the Mirwalk and miRDB bioinformatic algorithms. The expression levels of these miRNAs and c-Fos target gene in 30 OSCC tissues compared to their adjacent-normal tissue samples were analyzed by quantitative real-time PCR. In addition, the potential diagnostic values of miR-589-5p and miR-569 in OSCC as risk factors of carcinogenesis were assessed by ROC curve analysis. Results: c-Fos expression was significantly increased, while miR-589-5p and miR-569 gene expressions were decreased in tumor tissues compared to normal tissues. The increased c-Fos expression was also significantly correlated with tumor necrosis (p=0.034). We found that downregulation of miR-589-5p and miR-569 was negatively correlated with overexpression of the c-Fos target gene. The area under the curve (AUC) of mir-589-5p and mir-569 was 0.865 and 0.591, respectively. Conclusion: miR-589-5p may serve as a potent diagnostic and prognostic biomarkers for OSCC patients and be a potential approach to early diagnosis or prognosis of OSCC in the future. c-Fos overexpression may have a role in OSCC progression and necrosis.