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Prior to the COVID-19 pandemic, tuberculosis (TB) was the leading cause of death globally attributable to a single infectious agent, ranking higher than HIV/AIDS. Consequently, TB remains an urgent public health crisis worldwide. Oridonin (7a,20-Epoxy-1a,6b,7,14-tetrahydroxy-Kaur-16-en-15-one Isodonol, C₂₀H₂₈O₆, Ori), derived from the <i>Rabdosia Rrubescens</i> plant, is a natural compound that exhibits antioxidant, anti-inflammatory, and antibacterial properties. Our objective was to investigate whether Ori’s antioxidant and antibacterial effects could be effective against the infection <i>Mycobacterium marinum</i> (<i>Mm</i>)-infected cells and zebrafish. We observed that Ori treatment significantly impeded <i>Mm</i> infection in lung epithelial cells, while also suppressing inflammatory response and oxidative stress in <i>Mm</i>-infected macrophages. Further investigation revealed that Ori supplementation inhibited the proliferation of <i>Mm</i> in zebrafish, as well as reducing oxidative stress levels in infected zebrafish. Additionally, Ori promoted the expression of NRF2/HO-1/NQO-1 and activated the AKT/AMPK-α1/GSK-3β signaling pathway, which are both associated with anti-inflammatory and antioxidant effects. In summary, our results demonstrate that Ori exerts inhibitory effects on <i>Mm</i> infection and proliferation in cells and zebrafish, respectively. Additionally, Ori regulates oxidative stress by modulating the NRF2/HO-1/NQO-1 and AKT/AMPK-α1/GSK-3β signaling pathways.