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Objective This study aimed to assess the effect of a novel synthetic chalcone, Chalcone T4, on a murine model of periodontitis and on RANKL‐induced osteoclastogenesis in vitro. Background Chalcones are natural compounds with anti‐inflammatory properties, and its synthetic analogs with enhanced biological effects have potential as therapeutic agents. Periodontitis is characterized by chronic inflammation of the periodontium and alveolar bone resorption. Safe and effective anti‐inflammatory agents can have an important additive effect in the treatment in this disease. Methods Periodontitis was induced via the installation of a ligature around the first molar. Rats (n = 32) received Chalcone T4 (5 and 50 mg/kg) or distilled water by gavage daily for 15 days. Outcomes assessed were bone resorption (μCT), TNF‐α production (ELISA), cellular infiltrate, and collagen content (stereometric analysis, CD45+ cells by immunohistochemistry), and activation of NFATc1 and NF‐kB (immunohistochemistry). In vitro, RAW 264.7 were treated with Chalcone T4 and stimulated with RANKL for assessment of osteoclast differentiation (actin ring staining) and activity (pit assay). Results Chalcone T4 significantly reduced periodontitis‐associated bone resorption, as well as the cellular infiltrate, while increasing the collagen content. Production of TNF‐α, infiltration of CD45‐positive cells, and NF‐kB activation were markedly reduced. In vitro, chalcone T4 inhibited both osteoclast differentiation and activity. Conclusion Chalcone T4 significantly inhibited alveolar bone resorption and inflammation in vivo and RANKL‐induced osteoclastogenesis in vitro, suggesting a therapeutic role for this compound in the treatment of periodontitis.