Aim: At the moment there is no clear evidence with clinico-histological and immunohistochemical studies in animals to show the curcumin effect on the gingival overgrowth following phenytoin consumption. The purpose of the present study was to identify this subject. Materials and methods: In this experimental study, 50 adult male Wistar rats were divided into three groups. The rats in groups I and II received 100 mg/kg of phenytoin per day. Group II also received 20 mg/kg intraperitoneal curcumin per day. The control group received the curcumin vehicle only. Gingival clinical dimensions were measured at the beginning and end of the study. The rats were then sacrificed, biopsy of gingiva was prepared, and the samples were stained with hematoxylin–eosin. Morphometry was performed to evaluate the degree of inflammation, epithelial thickness, number, and cross-sectional area of the blood vessels. Immunohistochemical staining was performed using Ki67 and α-SMA. Results: Compared to the control group, Phenytoin in group I increased gingival volume. There was significance difference in group II with group I and control after intervention in the clinical view (p = 0.002). The difference in the number of blood vessels between groups I and II was statistically significant (p = 0.001). Significant differences were observed in blood vessel cross-sectional area (p = 0.001), epithelial thickness (p = 0.002), Ki67, and α-SMA expression between groups I and II (p = 0.001). Conclusion: In rats, curcumin seems to exerts its effects in preventing an increase in gingival volume caused by Phenytoin through decreasing the inflammatory infiltration, decreasing the number of blood vessels and increasing their cross-sectional area, decreasing the thickness of the epithelium, and decreasing the expression of Ki67 and α-SMA. Clinical significance: It is suggested that curcumin may be effective in treatment of gingival enlargement following Phenytoin consumption in future. Larger sample size and clinical trials study are recommended.