Objective To explore the mechanism by which osteoking ( OK) regulates ferroptosis and improves knee osteoarthritis (KOA). Methods We performed Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis by analyzing target genes related to OK, KOA, and ferroptosis through network pharmacology. Human C28 / I2 cells were used to simulate an in vitro arthritis model. Cells were divided into Control, model (interleukin ( IL)-1β 10 mg / L), IL-1β + OK, IL-1β + OK+ advanced glycation end products ( AGEs), IL-1β + Ferrostatin-1( Fer-1) and IL-1β + OK + Fer-1 groups. The inflammatory factor IL-6 and oxidative stress factors malondialdehyde (MDA), superoxide dismutase ( SOD), and glutathione ( GSH) in the cell supernatant were detected by enzyme-linked immunosorbent assay (ELISA). Fe ²⁺levels in each group were detected using cell-specific assay kits. Matrix metalloproteinase ( MMP13 ), cartilage matrix synthesis protein 2 ( COLA2 ), glutathione peroxidase 4 (GPX4), and solute carrier family 7 (SLC) proteins were detected by western blot. A rat model of KOA was created by medial meniscus instability surgery. Rats were divided into sham surgery, model and osteoking groups and treated with the corresponding drugs orally for 8 weeks. Paw-contraction reaction time and weight were measured in each group using a hot plate apparatus and pressure pain gauge, respectively. Serum inflammatory factors tumor necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF), IL-6, and the oxidative stress factors MDA,SOD, GSH, and reactive oxygen species (ROS) were detected by ELISA. Knee joints were stained with hematoxylin /eosin, safranin turquoise, and toluidine blue, and the degree of cartilage tissue degeneration was scored according to the OARSI standard. MMP13, COLA2, GPX4, SLC, AGEs, and their receptor (RAGE) proteins were detected in rat cartilage by Western blot. Results Network pharmacology analysis identified the AGEs-RAGE and other signaling pathways as potential key pathways by which OK may act on KOA and ferroptosis. In vitro, MDA, IL-6, and Fe²⁺levels increased in the IL-1 β group ( P<0. 05,P<0. 01), while GSH and SOD levels decreased ( P<0. 05,P<0. 01). MMP13 levels increased ( P<0. 05), while COLA2, GPX4, and SLC levels decreased ( P<0. 01). OK intervention reversed the above result and AGEs weakened the effect of OK, with significant effects on the relevant indicators. OK also enhanced the anti-inflammatory and antioxidant stress effects of the ferroptosis inhibitor Fer-1 on C28 / I2 cells, and improved the metabolic balance. DMM group rats showed significantly increased tenderness,thermal pain, and OARSI score (P<0. 01,P<0. 001), and damage to the cartilage surface and matrix of the knee joint. Compared with the DMM group, OK significantly reduced tenderness, thermal pain, and OARSI scores (P<0. 01), and alleviated damage to the cartilage surface and matrix of the knee joint. COLA2, GPX4, and SLC levels in the articular cartilage were significantly increased in the OK group compared with the DMM group ( P<0. 05), while MMP13, AGEs, and RAGE were decreased ( P<0. 05,P<0. 01). Serum levels of TNF-α, VEGF, IL-6,MDA, and ROS were significantly reduced in the OK group (P<0. 01), while SOD and GSH were increased (P<0. 01). Conclusions OK can inhibit ferroptosis and protect articular cartilage via the AGEs-RAGE axis, thereby exerting anti-arthritis effects.