Abstract: Background: Periodontitis is characterized by alveolar bone resorption, aggravated by osteoblast dysfunction, and associated with intracellular oxidative stress linked to nuclear factor erythroid-2-related factor 2 (NRF2) levels. We evaluated the molecular mechanism of periodontitis onset and development and the role of NRF2 in osteogenic differentiation. Methods: Primary murine mandibular osteoblasts were extracted and exposed to Porphyromonas gingiva lipopolysaccharide (Pg-LPS) or other stimuli. Reactive oxygen species and JC-1 staining were used to detect intracellular oxidative stress. Alkaline phosphatase and alizarin red S staining were used to detect the osteogenic differentiation of osteoblasts. Immunofluorescence and Western blotting determined changes in the mitogen-activated protein kinase (MAPK) pathway and related molecule activities. Immunofluorescence colocalization and co-immunoprecipitation were performed to examine the nuclear translocation of NRF2 and its interaction with dual-specific phosphatase 1 (DUSP1) in cells. Results: Ligated tissue samples showed higher alveolar bone resorption rate and lower NRF2 levels than healthy periodontal tissue samples. Pg-LPS increased intracellular oxidative stress levels and inhibited osteogenic differentiation, whereas NRF2 expression changes correlated with oxidative stress and osteogenesis rate changes. NRF2 promoted dephosphorylation of the MAPK pathway by nuclear translocation and upregulation of DUSP1 expression, thus enhancing the osteogenic differentiation capacity of mandibular osteoblasts. Interaction between NRF2 and DUSP1 was observed. Conclusions: NRF2 and its nuclear translocation may regulate the osteogenic differentiation of mandibular osteoblasts under Pg-LPS conditions by interacting with DUSP1 in a process linked to the MAPK pathway. These findings may form the basis of periodontitis treatment.