Purpose: Oral epithelial dysplasia (OED) occurs on exposure of epithelial cells to carcinogens and genetic alteration. Once the reversible cell damage is surpassed, cells either undergo apoptosis or transform into malignancy, chiefly oral squamous cell carcinoma (OSCC). Progressive accumulation of genetic errors (including mutations in TP53 and CDKN1A) is associated with the initiation and progression of potentially malignant oral lesions toward frank malignancy. The present study attempted to correlate the immunohistochemical expression of CDKN1A and TP53 with increasing severity of OED along with increased aggressiveness of OSCC as reflected in the clinicopathologic variables. Materials and Methods: Tissue sections from forty biopsy‑proven cases of OED and OSCC were stained with anti‑TP53 and anti‑CDKN1A mouse monoclonal antibodies. One hundred cells in each case were counted under high power magnification. Results: Poorly differentiated OSCC showed the highest TP53 expression (mean = 70.285), with least expression seen in mild dysplasia (mean = 22.125) (P < 0.001). Higher TP53 count was seen in cases with margin involvement, without recurrence and lymph node involvement and in cases which died of disease. CDKN1A expression was seen only in five cases and that too focally in the cytoplasm, thereby warranting removal of analysis of CDKN1A positivity from the study. Conclusion: The expression of TP53 in OED highlights its role in initial carcinogenesis. Although the role of CDKN1A in the cell cycle has been documented, its relationship to various clinical and pathological variables of OSCC and its different treatment modalities could not be adequately assessed.