Objective To investigate the effects of branding moxibustion therapy on the pathological progression of knee osteoarthritis (KOA) through modulation of OPN、NLRP3-related inflammatory signaling factors. Methods 6 month old New Zealand white rabbits were randomly divided into five groups (n=10 per group): control group, KOA group and treatment groups: branding moxibustion group, MCC950 group, combination group (branding moxibustion+MCC950). Magnetic resonance imaging (MRI) was performed to verify successful induction of the KOA model and to evaluate cartilage injury. We assessed histopathological changes in cartilage tissues using hematoxylin eosin (HE) staining and Alcian blue staining. We observed ultrastructural changes in chondrocyte mitochondria using transmission electron microscopy. Western blotting was used to detect the protein expression levels of osteopontin (OPN), NOD-like receptor pyrin domain-containing protein 3 (NLRP3), interleukin (IL)-1β, IL-18, collagen I (Collagen I), a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4), ADAMTS-5, matrix metalloproteinase-3 (MMP-3), and MMP-13 in cartilage tissues. Result Compared with the control group, the KOA group showed significantly increased WORMS and OARSI scores. Compared with the KOA group, all treatment groups exhibited significantly reduced WORMS and OARSI scores (all P < 0.05), with no significant differences among the treatment groups. Transmission electron microscopy demonstrated disrupted mitochondrial structures in chondrocytes of the KOA group and relatively intact mitochondrial morphology was observed in all treatment groups. Compared with the control group, OPN expression in cartilage tissues was decreased, the expression levels of NLRP3, IL-1β, and IL-18 were markedly increased in the KOA group. Compared with the KOA group, OPN expression was increased, while NLRP3, IL-1β, and IL-18 expression levels were significantly decreased in the treatment groups (all P < 0.05). IL-1β expression in the combination group was lower than that in the branding moxibustion group, whereas IL-18 expression in the MCC950 group was higher than that in both the branding moxibustion group and the combination group (all P < 0.05). Compared with the KOA group, Collagen I expression was increased in the control and treatment groups, with the most significant increase observed in the branding moxibustion group (P < 0.05). In addition, the expression levels of ADAMTS-4, ADAMTS-5, and MMP-3 in cartilage tissues were significantly lower in the control and treatment groups than in the KOA group (all P < 0.05), with no significant differences among the treatment groups. MMP-13 expression was lower in the control and treatment groups than in the KOA group, with the most pronounced reduction observed in the control and combination groups (all P < 0.05). Conclusion Branding moxibustion therapy may alleviate inflammatory responses and promote cartilage repair in KOA by modulating OPN、NLRP3-related inflammatory signaling factors and cartilage extracellular matrix degradation enzymes.