Ethnopharmacological relevance: Physalis angulata is an herb found in tropical and subtropical regions of the world; it is widely applied in popular medicine due to the therapeutic properties of the whole plant and its parts. Extracts and infusions of this plant have been extensively applied in folk medicine worldwide to treat inflammatory and immune-mediated diseases, including oral inflammatory conditions such as sore throat and gingivitis. Aim of the study: The present study was designed to investigate the protective effects of the ethanolic extract of P. angulata (EEPA) in a murine model of chronic periodontitis, aiming to corroborate its traditional use as an antiinflammatory and immunomodulatory agent, and to point out possible mechanisms involved in these effects. Materials and methods: EEPA was obtained from the stems of P. angulata collected in Bel´em (PA, Brazil). Chronic periodontitis was induced in male C57BL/6 mice by 12 administrations of lipopolysaccharide (LPS; 20 μg/1μL) into the gingival papilla in the course of 28 days. Starting from the 15th day after the first LPS injection, mice were daily treated with EEPA (50 or 100 mg/kg), nimesulide (25 mg/kg, reference drug), or vehicle by oral route for 14 days. At the end of the experimental period, alveolar bone loss was evaluated along with the gingival expression of biomarkers of periodontitis and cytokines by RT-q-PCR and ELISA. Hematological and biochemical parameters suggestive of systemic toxicity were also evaluated. The transcriptional activity of NF-κB was investigated using the luciferase assay in macrophages. Results: Mice with chronic experimental periodontitis suffered alveolar bone loss that was prevented by the treatment with EEPA (50 or 100 mg/kg) or nimesulide (25 mg/kg). EEPA (50 and 100 mg/kg) and nimesulide (25 mg/kg) reduced mRNA levels of MMP-9 mRNA, but not of TIMP-1 in gingival tissue of periodontitis-induced mice. Both treatments also reduced the production of the pro-inflammatory cytokines IL-1β and IL-6. The treatment with EEPA (100 mg/kg) increased the production of the anti-inflammatory cytokine TGF-β. No hematological or biochemical alterations were caused by the daily treatment with EEPA. In vitro luciferase assay suggested that a putative mechanism of EEPA is reducing the transcriptional activity of NF-κB. Conclusions: EEPA exhibited a disease-modifying effect in the chronic experimental periodontitis, along with unidentifiable systemic toxicity. This work corroborates the traditional use of P. angulata in oral inflammatory conditions and provides mechanistic hypotheses to explain its therapeutic effects.