Periodontitis is linked to various systemic conditions, but its impact on skeletal muscle remains unclear. Here, we utilized a ligature-induced periodontitis model in male mice and showed that periodontitis significantly reduces muscle and bone mass without affecting fat mass or food intake. Interestingly, activin A, well-documented inducer of muscle atrophy, is highly expressed in periodontitis-affected gingiva. The activin A gene (Inhba) is predominantly expressed in gingival fibroblasts and epithelial cells, which undergo significant proliferation as periodontitis progresses, as well as in myeloid cells infiltrating inflamed periodontal tissues and myeloid cell-derived osteoclasts. A similar upregulation pattern of INHBA was also confirmed in periodontitis-affected human tissues by scRNA-seq analysis. Furthermore, we demonstrated that serum activin A levels are increased in periodontitis-affected mice and patients. Gingival overexpression of activin A via AAV-Inhba transduction activates canonical activin signaling in skeletal muscle, as evidenced by increased pSMAD3 and MuRF1 expression, leading to significant muscle loss. Notably, intra-gingival injection of siInhba significantly reduced serum activin A levels and restored muscle mass and myofiber size. Our findings indicate that activin A is a mediator of muscle atrophy in periodontitis and suggest that local injection of siInhba may prevent periodontitis-induced muscle atrophy without apparent systemic adverse effects.