Background: Oral cancer is one of most prevalent cancer with high morbidity and mortality rate in India. Around 90% are squamous cell carcinomas among the oral cancers. Uncontrolled proliferation of cell is considered to be the key processes of oncogenesis. MIB-1 or Ki67 is expressed in all proliferating cells and used as a tool for estimating the percentage of dividing cells within a tumor. In addition to it, MIB-1 acts as a potentially prognostic marker in oral malignancies. Materials and Methods: Around 100 cases of oral squamous cell carcinoma were assessed for nuclear atypia, mitotic activity and necrosis. For Ki-67, strong nuclear positivity was seen as favorable. There were three grades: 1 for 10–30%, 2 for 30–50%, and 3 for 50% and above. The number of positive cells and staining intensity for p16 (nuclear or/and cytoplasmic staining) were computed. Results: Ki-67 and p16 expressions were seen in oral squamous cell carcinomas that are well, moderately, and poorly differentiated. Ki-67 expression increased when grades rose from well differentiated to poorly differentiated carcinoma. p16 had a better expression in well differentiated carcinoma compared to poorly differentiated carcinoma. The mean mitotic count, were increased in high grade neoplasms. Conclusions: Therefore, the expression of p16 and Ki-67 in malignant lesions of the oral squamous cell carcinoma can be used in conjunction with the histomorphological attributes to research their capacity for proliferation of oral malignancies.