Objectives: To investigate the expression of Bcl-2 in squamous cell carcinoma of the oral cavity. Methodology: This descriptive cross-sectional study was conducted at the Department of Histopathology, Pakistan Institute of Medical Sciences, Islamabad, from December 2021 to June 2022. Sixty patients aged 30 to 85 years, of both genders, diagnosed with squamous cell carcinoma of the oral cavity based on histopathology reports, were included. Immunohistochemistry for Bcl-2 was performed and assessed. All results were subsequently analyzed using SPSS Version 20. Results: Out of the 60 cases studied, 36 were males (60%) and 24 were females (40%). The mean age of the patients was 55 years. The most common histological grade was well-differentiated squamous cell carcinoma, accounting for 26 out of 60 cases (43.3%), followed by moderately differentiated squamous cell carcinoma (21/60, 35%). Poorly differentiated squamous cell carcinoma was the least common grade, found in 13 out of 60 cases (21.7%). Bcl-2 expression was positive in 23 patients (38.3%). Regarding grade-wise expression of Bcl-2, there was an increasing expression with increasing grades of oral squamous cell carcinoma: 19% Bcl-2 expression in well-differentiated squamous cell carcinoma, 38% in moderately differentiated squamous cell carcinoma, and 77% in poorly differentiated carcinomas. This demonstrated a significant correlation between Bcl-2 expression and histopathological grades (p value <0.001). Conclusion: In summary, Bcl-2 expression was detected in 38.3% of oral squamous cell carcinoma cases. Its immuno-expression is significantly associated with the histopathological grades of oral squamous cell carcinoma. Therefore, Bcl-2 can be considered an important prognostic marker as well as a potential target for chemoresistance cases through Bcl-2 inhibition.