Background: Periapical granuloma and periapical cysts develop as a sequela of inflammation of dental pulp, usually a consequence of an infected root canal. Mast cells (MCs) have most frequently been implicated in the pathophysiology of periapical lesions such as periapical granulomas and cysts. Aims: The present study was undertaken to emphasize the presence and quantification of MCs in periapical lesions (granulomas and cysts) using toluidine blue stain, with an aim to elucidate their role in the pathogenesis of these lesions. Materials and Methods: The study comprised a total of 55 previously diagnosed cases (30 cases of radicular cyst and 25 cases of periapical granuloma) selected from the departmental archives. The MCs were quantified in all the sections in the three zones, namely the epithelial, subepithelial, and deeper connective tissue zones. The results were sent for statistical analysis. Statistical Analysis: Wilcoxon paired t -test and Mann–Whitney U test were applied for intra- and intergroup comparison MCs in different zones of periapical granulomas and radicular cyst, respectively. Results: A statistically significant difference was observed between the two lesions in all the three zones, i.e., epithelial, subepithelial, and in deeper connective tissue zone with P = 0.001. Conclusion: Although MCs were present in all the three zones of both periapical cysts and granuloma, they were predominantly observed in radicular cysts than in periapical granuloma. This suggests a significant role of MC in initiation, development, and progression of these periapical lesions.