This study aimed to explore naringin’s potential to promote the osteogenic differentiation of MC3T3-E1 under oxidative stress. It delved into Nar’s connection with the Wnt/β-catenin and PI3K/Akt signaling pathways. Initially, 2911 OP-related genes were analyzed, revealing close ties with the PI3K/Akt and Wnt pathways alongside oxidative stress. Nar’s potential targets—ESR1, HSP90AA1, and ESR2—were identified through various databases and molecular docking studies confirmed Nar’s affinity with ESR1 and HSP90AA1. Experiments established optimal concentrations for Nar and H 2O 2. H 2O 2 at 0.3 mmol/L damaged MC3T3-E1 cells, alleviated by 0.1 µmol/L Nar. Successful establishment of oxidative stress models was confirmed by DCFH-DA probe and NO detection. Nar exhibited the ability to enhance osteogenic differentiation, counteracting oxidative damage. It notably increased osteoblast-related protein expression in MC3T3-E1 cells under oxidative stress. The study found Nar’s positive influence on GSK-3β phosphorylation, β-catenin accumulation, and pathway-related protein expression, all critical in promoting osteogenic differentiation. The research concluded that Nar effectively promotes osteogenic differentiation in MC3T3-E1 cells under oxidative stress. It achieved this by activating the Wnt/β-catenin and PI3K/Akt pathways, facilitating GSK-3β phosphorylation, and enhancing β-catenin accumulation, pivotal in osteogenesis.