Objective To investigate the effects of Yishen Zhuyu Tongluo Decoction on chondrocyte pyroptosis and ferroptosis in rats with knee osteoarthritis (KOA). Methods Forty SD were divided randomly into a sham operation group (n=10) and a modeling group (n=30). A KOA model was established in the modeling group by anterior cruciate ligament transection of the right hind limb knee joint. The drawer test was used to confirm the successful establishment of the model. Post-surgery, the rats were subjected to 30 min of forced activity daily to induce KOA. Lameness and hopping movements were observed after 4 weeks, and hematoxylin and eosin staining confirmed cartilage surface damage, deformation, and inflammatory cell infiltration, indicating successful modeling. The model rats were then assigned randomly to a model group (n=8), celecoxib group (n=8), and Yishen Zhuyu Tongluo Decoction group (n=8). The sham operation and model groups received 10 mL/kg of saline by gavage, the celecoxib group received 12 mg/kg of celecoxib solution, and the Yishen Zhuyu Tongluo Decoction group received 5.4 g/kg of the herbal decoction, once daily for 8 weeks. After the interventions, the rats were anesthetized, blood was collected from the abdominal aorta and serum was separated, and the knee joints were isolated. Three samples were fixed in paraformaldehyde, while the remaining cartilage tissue was reserved. Pathological changes in joint cartilage were observed by hematoxylin and eosin and Safranin O-Fast Green staining. Bone microstructure was analyzed using micro-computed tomography. Serum interleukin (IL)-1β and IL-18 protein levels were detected by enzyme-linked immunosorbent assay. Relative mRNA expression levels ofNLRP3, ASC, Caspase-1, GSDMD, IL-1β, IL-18, ACSL4, FTH-1, GPX-4, and cyclooxygenase (COX)-2 were detected by reverse transcription quantitative real-time PCR, and protein expression of NLRP3, Caspase-1, and COX-2 were detected by immunohistochemistry. Results Compared with the sham operation group, model rats showed surface damage and deformation of cartilage tissue, disordered cell arrangement in all layers, significant loss of Safranin O-Fast Green staining, and sparse and irregular trabecular bone distribution. Serum levels of the inflammatory factors IL-1β and IL-18 were elevated (P<0.01). mRNA expression levels of NLRP3, ASC, Caspase-1, GSDMD, IL-1β, IL-18, ACSL-4, and COX-2 were also significantly increased (all P<0.01), while FTH-1 and GPX-4 mRNA expression levels were decreased (P<0.01). Compared with the model group, rats in the celecoxib and Yishen Zhuyu Tongluo Decoction groups showed smoother and more intact cartilage surfaces, significantly increased cell counts, less loss of Safranin O-Fast Green staining, denser trabecular bone, and thicker cortical bone, with improved bone microstructure. Serum IL-1β and IL-18 levels were reduced (P<0.01), NLRP3 (P<0.01, P<0.05), ASC, Capase-1, GSDMD, IL-1β, IL-18, ACSL-4, and COX-2 mRNA levels were decreased (all P<0.01), and relative expression levels of FTH-1 and GPX-4 mRNA were significantly increased (P<0.01). Conclusions Yishen Zhuyu Tongluo Decoction can treat KOA by inhibiting chondroptosis and ferroptosis in chondrocytes, reducing serum IL-1β and IL-18 levels, and improving bone microstructure.