Natural compounds capable of modulating the host response have received considerable attention, and herbal products are suggested as adjunctive agents in periodontal disease treatment. Objective: This study aimed to demonstrate the effect of grape seed extract (GSE) on periodontitis. Material and Methods: Ligature induced periodontitis was created in 40 rats and they were assigned to four equal groups. One group was fed laboratory diet (group A) while three groups received GSE additionally. Silk ligatures were placed around the cervical area of the mandibular first molars for four weeks to induce periodontitis. The GSE groups were reallocated regarding GSE consumption as: for two weeks before ligation (group B; totally eight weeks), from ligation to two weeks after removal of the ligature (group C; totally six weeks), and for two weeks from ligature removal (group D; totally two weeks). Sections were assessed histologically and immunohistochemically. Inflammatory cell number (ICN), connective tissue attachment level (CAL), osteoclast density (OD), IL-10 and TGF-beta stainings in gingival epithelium (GE), connective tissue (GC), and periodontal ligament (PL) were used as the study parameters. Results: Lower ICN, higher CAL, and lower OD were observed in the GSE groups (p<0.05). IL-10 was more intensive in the GSE groups and in the GEs (p<0.05). Group B showed the highest IL-10 for PL (p<0.05). TGF-beta was higher in the GEs of all groups (p<0.017). Conclusions: The results suggest anti-inflammatory activities of GSE, but further investigations are needed for clarification of these activities.