Ferroptosis-induced lipid peroxidation in chondrocytes exacerbates intra-articular inflammation, oxidative stress, and articular cartilage degradation, accelerating osteoarthritis (OA) progression. Effective anti-inflammatory and antioxidant interventions can alleviate both joint pain and cartilage damage. This study aims to elucidate the therapeutic effects of Notopterol (NP), a bioactive compound extracted from the rhizome of Notopterygium incisum, a traditional Chinese medicine known for its potent anti-inflammatory and antioxidant properties, in treating OA. An in vivo mouse model of OA was established through medial meniscus destabilization (DMM). Intra-articular injections of NP over a 4-week treatment period significantly alleviated pain and gait abnormalities, reduced subchondral osteosclerosis, and attenuated cartilage degradation compared to the untreated DMM group. In vitro, chondrocytes treated with IL-1β to simulate OA conditions exhibited increased viability following NP pretreatment, with concurrent reductions in apoptosis, reactive oxygen species (ROS) accumulation, and chondrocyte catabolic dysfunction, along with enhanced extracellular matrix (ECM) synthesis. Mechanistically, NP exerts its anti-OA effects by inhibiting PI3K/Akt phosphorylation, suppressing ferroptosis, and improving antioxidant defense via upregulation of glutathione (GSH) and glutathione peroxidase 4 (GPX4), thereby preventing lipid peroxidation. In conclusion, NP modulates the PI3K/Akt/GPX4 axis to protect against lipid peroxidation, inhibit ferroptosis, and preserve cartilage integrity, thus delaying OA progression.