Periodontitis, a chronic inflammatory disease affecting up to 40% of adults over 60, is characterized by gingival inflammation, periodontal damage, and alveolar bone resorption. The nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2)/Kelch-like ECH-Associated Protein 1 (KEAP1) (NRF2/KEAP1) signaling pathway plays a crucial role in modulating redox balance and inflammation in periodontitis. However, NRF2 expression is decreased in gingival tissues of periodontitis patients, while oxidative stress is significantly increased. This review examines the role of natural and synthetic compounds in modulating the NRF2/KEAP1 pathway in in vitro and in vivo models of periodontitis to evaluate potential new treatments. Natural compounds such as quercetin, biochanin A, curcumin, 10-oxo-trans-11-octadecenoic acid (KetoC), caffeic acid phenethyl ester (CAPE), paonol, resveratrol, sulforaphane (SFN), dehydrocrocostus lactone, hesperetin, notopterol, isorhamnetin, magnolol, sappanchalcone, kynurenic acid (KA), epigallocatechin-3-gallate (EGCG), silibinin, chlorogenic acid (CA), baicalein, and magnolol have been shown to activate the NRF2/KEAP1 pathway, reducing inflammation, oxidative stress, and bone loss in periodontitis models. These compounds can inhibit RANKL-induced osteoclast formation, reduce alveolar bone loss, and improve antioxidant status. Additionally, NRF2 activation has been found to inhibit pyroptosis through the NLRP3 inflammasome pathway, reducing pro-inflammatory cytokine production. In diabetic patients with periodontitis, NRF2 activation can mitigate oxidative damage and reduce cell senescence, promoting periodontal tissue repair and regeneration. Overall, natural compounds that activate the NRF2/KEAP1 pathway show promise as potential treatments for periodontitis, and further clinical trials are needed to evaluate their efficacy in humans.Periodontitis, a chronic inflammatory disease affecting up to 40% of adults over 60, is characterized by gingival inflammation, periodontal damage, and alveolar bone resorption. The nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2)/Kelch-like ECH-Associated Protein 1 (KEAP1) (NRF2/KEAP1) signaling pathway plays a crucial role in modulating redox balance and inflammation in periodontitis. However, NRF2 expression is decreased in gingival tissues of periodontitis patients, while oxidative stress is significantly increased. This review examines the role of natural and synthetic compounds in modulating the NRF2/KEAP1 pathway in in vitro and in vivo models of periodontitis to evaluate potential new treatments. Natural compounds such as quercetin, biochanin A, curcumin, 10-oxo-trans-11-octadecenoic acid (KetoC), caffeic acid phenethyl ester (CAPE), paonol, resveratrol, sulforaphane (SFN), dehydrocrocostus lactone, hesperetin, notopterol, isorhamnetin, magnolol, sappanchalcone, kynurenic acid (KA), epigallocatechin-3-gallate (EGCG), silibinin, chlorogenic acid (CA), baicalein, and magnolol have been shown to activate the NRF2/KEAP1 pathway, reducing inflammation, oxidative stress, and bone loss in periodontitis models. These compounds can inhibit RANKL-induced osteoclast formation, reduce alveolar bone loss, and improve antioxidant status. Additionally, NRF2 activation has been found to inhibit pyroptosis through the NLRP3 inflammasome pathway, reducing pro-inflammatory cytokine production. In diabetic patients with periodontitis, NRF2 activation can mitigate oxidative damage and reduce cell senescence, promoting periodontal tissue repair and regeneration. Overall, natural compounds that activate the NRF2/KEAP1 pathway show promise as potential treatments for periodontitis, and further clinical trials are needed to evaluate their efficacy in humans.