Background Due to the high mortality rate of oral squamous cell carcinoma (OSCC), early detection of the disease is critical. Despite previous research on potential diagnostic biomarkers, there is no consensus regarding the role and validity of specific biomarkers for OSCC. Aims The purpose of this study was to explore and verify diagnostic biomarkers for OSCC. Methods and Results mRNA expression data of 57 oral tissues from OSCC patients and 22 from individuals without OSCC was analyzed using a moderated t-test to determine potential biomarkers. Statistical analysis revealed 163 differentially expressed genes between OSCC and normal tissues, 68 of which were upregulated in OSCC tissue. The 11 most significantly upregulated genes were determined to be MMP1, MMP3, MMP10, CXCL10, IL8, CXCL11, MMP12, CXCL9, GBP5, RPS4Y1, and MMP13. Conclusions This study suggests that MMPs are especially promising diagnostic biomarkers and therapeutic targets for OSCC and identifies 68 upregulated genes for further research.