Background: Oral cancer is a significant global health issue, with India accounting for nearly one-third of global cases. The late-stage diagnosis common in India leads to poor survival outcomes, highlighting the need for early detection and effective biomarkers. Introduction: This study explores the potential of serum β2-microglobulin (β2M) and lipid-bound sialic acid (LSA) as diagnostic and prognostic biomarkers in oral carcinoma, with a focus on the Indian population, where the disease burden is exceptionally high. Methodology: This case-control study involved 200 subjects (100 oral cancer cases and 100 healthy controls) aged 20-60 years. Serum β2M and LSA levels were measured using ELISA kits. Statistical analysis, including ROC analysis and correlation studies, was performed using SPSS software to assess the diagnostic accuracy and clinical relevance of these biomarkers. Results: Serum β2M and LSA levels were significantly higher in oral cancer cases compared to controls, with β2M showing near-perfect diagnostic accuracy (AUC 0.999) and LSA demonstrating excellent accuracy (AUC 0.945). Both biomarkers strongly correlated with advanced AJCC stages, underscoring their potential in assessing disease severity and aiding early detection. Conclusion: Serum β2M and LSA levels are promising biomarkers for the diagnosis and assessment of oral carcinoma. Their incorporation into clinical practice could enhance early detection, prognosis, and treatment monitoring, ultimately improving patient outcomes. Further research with larger cohorts is needed to validate these findings and explore their longitudinal applicability.