<p>Oral squamous cell carcinoma (OSSC) is a significant global health concern, particularly in the Indian subcontinent where it accounts for nearly 40% of all cancers. While histopathology is the diagnostic gold standard, there is a critical need for cost-effective, non-toxic screening tools for early detection in resource-limited settings. This study evaluates the efficacy of Methylene Blue staining as a diagnostic adjunct for identifying oral precancerous and cancerous lesions. A clinicopathological study was conducted at ENT Department, involving 100 participants presenting with suspected oral malignancies. Lesions were stained with 1% Methylene Blue, followed by a 1% acetic acid rinse to eliminate mechanically retained stain. Dark blue staining was considered positive. The study population showed a male predominance (71.0%) and was primarily middle-aged (83.0% aged 31–60 years). The most common symptom was ulceration (96.67%), and the buccal mucosa (45%) was the most frequent site of lesion. Methylene Blue staining demonstrated an overall accuracy of 93.75%, with a high sensitivity of 96.3% and a positive predictive value (PPV) of 96.3%. Specificity and negative predictive value (NPV) were reported at 80.0% and 79.9%, respectively. Statistical analysis confirmed significant performance for both premalignant (<i>p</i> = 0.014) and malignant (<i>p</i> = 0.010) lesions. Methylene Blue staining is an effective, non-invasive screening tool for oral cancer. In this study, the technique demonstrated high sensitivity and statistical accuracy in identifying both premalignant and malignant oral mucosal lesions.</p>