Periodontitis as a chronic inflammatory disease leads to the destruction of the supportive tissues of affected teeth. Crosstalk between periodontitis and the host immune system plays a crucial role in the pathogenesis of this disease. Since polyphenol components such as silymarin and resveratrol have anti-bacterial and anti-inflammatory effects on periodontal tissues, the purpose of this study was to investigate the anti-histaminic effects of silymarin and resveratrol on human gingival fibroblasts (HGFs). HGFs were treated with a concentration of silymarin or resveratrol (100 μg/ml) and a combination of these two polyphenols (50/100 or 100/200 μg/ml silymarin/resveratrol). The effect of silymarin and resveratrol on cell viability was assessed by MTT assay. Also, HGFs were treated with silymarin and/or resveratrol and were stimulated by histamine. The levels of interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-α), and tissue plasminogen activator 1 (TPA-1) were assessed by enzyme-linked immunosorbent assay (ELISA). After treatment with silymarin, the viability of fibroblast cells significantly increased, whereas treatment with resveratrol and combinations of these flavonoids (silymarin 50 μg/ml and resveratrol 100 μg/ml) did not have any significant effect on cell viability after 24 h. Treatment with 100/200 μg/ml silymarin/resveratrol significantly decreased the cell viability after 48 h. Resveratrol inhibited histamine-induced IL-6 secretion by HGFs significantly, whereas silymarin showed significant effect on TNF-α. A blend of silymarin and resveratrol displayed more valuable results. In conclusion, combination of resveratrol and silymarin could significantly inhibit inflammatory effects of histamine on cultured HGFs by reduction of IL-6, IL-8, TPA-1, and TNF-α.