Oral squamous cell carcinoma (OSCC) is a significant health concern, with various factors influencing its development and progression. Understanding these factors, including p16 expression and clinicopathologic features, is crucial for improved diagnosis and treatment. Objective: To compare various grades of OSCC based on immunohistochemical expression of p16 and clinicopathologic parameters. Methods: The comparative cross-sectional study was conducted at the Department of Pathology, Peshawar Medical College (PMC), and Peshawar Dental College (PDC) from August 2020 to August 2021. It included 53 cases of OSCC with documented snuff use history. Tumor sections were stained with Hematoxylin and Eosin and underwent immunohistochemical staining for p16 expression. Sample size calculation utilized G Power software. Statistical analysis was performed using SPSS version 20.0, employing the Chi-Square test to assess categorical variables. Results: Among the 53 OSCC cases, the majority were male (66.0%) with ages ranging from 26 to 85 years, the most common age group being 51-70 years. The tongue was the primary site for OSCC development. Well-differentiated cases were predominant (64.2%), followed by moderate (20.8%) and poor grade cases (15.1%). However, no significant association was found between p16 expression and OSCC grades. Notably, p16 expression tended to be higher in snuff users and well-differentiated OSCC cases, although not statistically significant. Conclusions: Well-differentiated OSCC cases exhibited the highest expression of p16, followed by moderate and poorly differentiated cases. However, no significant correlation was observed between p16 expression and OSCC in snuff users.