Periodontitis is a chronic inflammatory disease affecting up to 40% of adults over 60 years old, characterized by periodontal damage and alveolar bone resorption. The NRF2/KEAP1 signaling pathway plays a key role in regulating redox balance and inflammation in periodontitis. However, NRF2 expression is decreased in periodontitis, while oxidative stress is increased. Oxidative stress and lipopolysaccharides (LPS) from gram-negative bacteria contribute to periodontal inflammation and alveolar bone loss. This review discusses the role of natural and synthetic compounds in modulating the NRF2/KEAP1 pathway in periodontitis models to develop new treatments. Several natural compounds, such as quercetin, biochanin A, curcumin, ketoC, CAPE, paeonol, EFL1, resveratrol, sulforaphane, and others, have been shown to activate the NRF2/KEAP1 pathway, reducing oxidative stress, inflammation, and alveolar bone loss. These compounds also inhibit RANKL-induced osteoclastogenesis and promote osteogenesis. NRF2 activation can inhibit NF-κB signaling, reducing inflammatory cytokines and promoting periodontal tissue repair. In diabetes-associated periodontitis, NRF2 activation can reduce oxidative stress and cell senescence, improving periodontal tissue repair. The review highlights the potential of natural compounds in modulating the NRF2/KEAP1 pathway for the prevention and treatment of periodontitis. Further clinical trials are needed to evaluate the efficacy of these compounds in humans.Periodontitis is a chronic inflammatory disease affecting up to 40% of adults over 60 years old, characterized by periodontal damage and alveolar bone resorption. The NRF2/KEAP1 signaling pathway plays a key role in regulating redox balance and inflammation in periodontitis. However, NRF2 expression is decreased in periodontitis, while oxidative stress is increased. Oxidative stress and lipopolysaccharides (LPS) from gram-negative bacteria contribute to periodontal inflammation and alveolar bone loss. This review discusses the role of natural and synthetic compounds in modulating the NRF2/KEAP1 pathway in periodontitis models to develop new treatments. Several natural compounds, such as quercetin, biochanin A, curcumin, ketoC, CAPE, paeonol, EFL1, resveratrol, sulforaphane, and others, have been shown to activate the NRF2/KEAP1 pathway, reducing oxidative stress, inflammation, and alveolar bone loss. These compounds also inhibit RANKL-induced osteoclastogenesis and promote osteogenesis. NRF2 activation can inhibit NF-κB signaling, reducing inflammatory cytokines and promoting periodontal tissue repair. In diabetes-associated periodontitis, NRF2 activation can reduce oxidative stress and cell senescence, improving periodontal tissue repair. The review highlights the potential of natural compounds in modulating the NRF2/KEAP1 pathway for the prevention and treatment of periodontitis. Further clinical trials are needed to evaluate the efficacy of these compounds in humans.