This study investigates the use of a piezoelectric hydrogel to treat periodontitis by enhancing mitochondrial bioenergetics and modulating the immune microenvironment. The hydrogel, composed of tilapia gelatin and tetragonal BaTiO3 (t-BTO) nanoparticles, generates piezopotential under mechanical stress, which promotes osteogenic differentiation of inflammatory periodontal ligament stem cells (PDLCs) by modulating energy metabolism and ATP synthesis. Additionally, it shifts macrophages from an M1 to an M2 phenotype, creating an anti-inflammatory and pro-regenerative niche. In vitro, the piezoelectric stimulation and tilapia gelatin synergistically enhanced osteogenesis and reduced inflammation in PDLCs and RAW 264.7 macrophages. In vivo, the piezoelectric hydrogel significantly improved bone regeneration and reduced inflammation in a rat model of periodontitis. These findings suggest that the piezoelectric hydrogel is a promising approach for treating periodontitis by modulating bioenergetics and immunomodulation.This study investigates the use of a piezoelectric hydrogel to treat periodontitis by enhancing mitochondrial bioenergetics and modulating the immune microenvironment. The hydrogel, composed of tilapia gelatin and tetragonal BaTiO3 (t-BTO) nanoparticles, generates piezopotential under mechanical stress, which promotes osteogenic differentiation of inflammatory periodontal ligament stem cells (PDLCs) by modulating energy metabolism and ATP synthesis. Additionally, it shifts macrophages from an M1 to an M2 phenotype, creating an anti-inflammatory and pro-regenerative niche. In vitro, the piezoelectric stimulation and tilapia gelatin synergistically enhanced osteogenesis and reduced inflammation in PDLCs and RAW 264.7 macrophages. In vivo, the piezoelectric hydrogel significantly improved bone regeneration and reduced inflammation in a rat model of periodontitis. These findings suggest that the piezoelectric hydrogel is a promising approach for treating periodontitis by modulating bioenergetics and immunomodulation.