Background: To find the association of tumor budding, depth of invasion (DOI), and epithelial-to-mesenchymal transition (EMT) markers (E-cadherin and smooth muscle actin [SMA] expression) with prognostic factors of oral squamous cell carcinoma (OSCC). Materials and Methods: A cross-sectional study conducted on 50 cases of histologically proven OSCC were selected for the assessment of TNM staging, tumor budding, DOI, and EMT markers (E-cadherin and SMA expression). Associations were evaluated between established clinical prognostic factors and histological parameters. Statistical analysis was performed using SPSS version 21.0. (IBM, Chicago, Illinois, USA) and P < 0.05 was considered statistically significant. Results: In the study, the median age of distribution was 48.5 years with 86% of males. Tobacco consumption was seen among 90% of patients. A significant association of pathological TNM staging with tumor budding and DOI (P < 0.05). There was a loss of E-cadherin expression with loss of tumor differentiation, progressive TNM stage, increasing DOI and more tumor budding (P < 0.05). On the contrary, α-SMA (% stained cells) expression showed an increase with increasing pathological T stage, N stage, tumor budding, and DOI (P < 0.0001). However, the tumor differentiation showed no significant association with SMA expression (P = 0.44). Conclusion: It can be concluded that EMT has a strong association with OSCC demonstrated by loss of E-cadherin and increased expression of α-SMA at the invasive front in higher grade carcinomas, in tumors with increased DOI, high-risk tumor budding, and increased pathological T and cases showing lymph node metastasis. Hence, SMA can be used in conjunction with loss of E-cadherin expression for determining the aggressive nature of OSCC and predicting the survival rates of the patients.