Background: E-Cadherin/β-Catenin protein complexes play a major role in epithelial to mesenchymal transition (EMT) and vice versa. Such types of EMT are implicated physiologically during embryonic development and pathologically in tissue fibrosis and tumorigenesis. Aims: The aim was the evaluation of E-Cadherin and β-Catenin immunoreactivity in various grades of oral squamous cell carcinoma (OSCC) and to correlate their pattern of expression. Materials and Methods: Immunohistochemical expression of E-Cadherin/β-Catenin was evaluated in a total n = 30 tissue samples comprising of n = 10 well-differentiated squamous cell carcinoma (WDSCC), n = 10 moderately differentiated squamous cell carcinoma (MDSCC), and n = 10 poorly differentiated squamous cell carcinoma (PDSCC). Based on the intensity of staining, an immunoreactivity scoring was calculated. Statistical Analysis: The scorings obtained were subjected to independent t-test, paired t-test, Chi-square test, and ANOVA test using SPSS version 20.0 statistical analysis software. P < 0.05 was considered statistically significant. Results: A significant difference was observed in the expression of β-Catenin between normal mucosa and WDSCC; normal mucosa and MDSCC. A gradual decrease in the immunoreactivity score of E-Cadherin is seen in WDSCC, MDSCC, and PDSCC. Conclusion: Therefore, dysregulation of these proteins can lead to tumor progression, invasion, and metastasis. Further studies are warranted to specify the role of these EMT proteins as prognostic/therapeutic markers in patients suffering from OSCC.