Introduction:Oral Squamous Cell Carcinomais a major health challenge with high recurrence and poor prognosis.Asper Globocan 2022, lip and oral cancer ranked 16th in terms of incidence with 389,485(2%)newcases. p16 helps identify HPV infection and induces apoptosis, while Ki-67, a key cell cycle regulator, is crucial for assessing cell proliferation, tumor development and prognosis. Aim: The study aims to evaluate the immunohistochemical expression of p16 and Ki-67 in oral squamous cell carcinoma and correlation with various clinicopathological parameters. Material and Methods: This descriptive analysis was conducted at Muzaffarnagar Medical College & Hospital, involving 50 histologically confirmed oral squamous cell carcinoma cases. The study involved p16 and Ki-67 expression through immunohistochemistry on histologically diagnosed OSCC cases and scoring was done. Results: The study found that most OSCC patients belong to fifth and sixth decades of life, with buccal mucosa being the most affected site. Tobacco use was prevalent among the patients. Most cases were moderately differentiated. p16 and Ki-67 expression werehigher in poorly differentiated cases. Positive p16 expression was observed in 38% of the cases but showed no significant correlation with age, gender, or histological grade. However, significant associations were found between age, histological grade, and Ki-67 expression. Conclusion: This study concluded that p16 expression was positive in 38% of OSCC cases, with higher rates in poorly differentiated tumors, but no significant links to age, gender, or histological grade. Ki-67 levels, higher in poorly differentiated cases, were significantly associated with age, indicating more aggressive disease in older ones.