BackgroundOral cancer is a common malignancy worldwide, with approximately 3,50,000 new cases diagnosed yearly. Out of many factors which affect the survival in patients with oral cancer, lymph node metastases are a major factor that reduces survival by 50%. Even though many biomarkers have been studied to predict lymph node metastasis, none have yet been accepted for routine use. Matrix metalloproteinases (MMPs) play a vital role in extracellular matrix (ECM) degradation, thus facilitating the invasive potential and the metastatic cascade of tumors. Of the different subtypes, multiple studies have demonstrated that matrix metalloproteinase 9 (MMP9) overexpression is often associated with the aggressive nature of the tumor. Therefore, this investigation is done to know the role of MMP9 in predicting lymph node metastasis in oral squamous cell carcinoma (OSCC). AimTo determine the immunohistochemical expression of MMP9 in OSCC and to find its association with lymph node metastasis. Settings and designIt is a laboratory-based observational study. Materials and methodsOne hundred five histologically proven cases of OSCC were studied. Histopathological parameters like depth of invasion, presence of lymph node metastasis, grading, and TNM staging were done according to the 8th AJCC staging criteria. Both intensity and proportion of MMP9 expression were recorded. Statistical analysisFor qualitative data, the Chi-square test was used as a test of significance. The p-value (probability that the result is true) of <0.05 was considered statistically significant after assuming all the rules of statistical tests. ResultsA higher expression of MMP9 was observed in 56.2% of cases and the higher expression correlated with the presence of lymph node metastases (p<0.001), an advanced stage of cancer (P <0.001), and grade of the tumor (p=0.003). ConclusionA positive association between MMP9 and lymph node metastasis and pathological TNM staging demonstrates MMP9 as a potential biomarker to predict the behavior of the tumor.