OA is a highly prevalent, debilitating joint disease with a substantial and escalating socioeconomic burden. Characterized by progressive cartilage degradation, synovial inflammation, and subchondral bone changes, OA is a leading cause of chronic pain and disability, significantly impacting quality of life and healthcare costs. Despite this immense burden, current treatments primarily focus on symptomatic relief, with limited efficacy in altering disease progression. The complex, multifactorial nature of OA pathogenesis has further impeded the development of effective disease-modifying osteoarthritis drugs (DMOADs) to prevent or significantly delay cartilage degeneration and joint damage. Therefore, in this work, we investigated the potential of a combination therapy simultaneously targeting both catabolic and anabolic processes to ameliorate OA. Our findings demonstrate that the combination of Dox and IGF-1 synergistically inhibited key aspects of OA pathogenesis, including matrix degradation and inflammation, while enhancing matrix retention. This effect was also validated in human OA cartilage explants, highlighting its translational potential. Mechanistically, the drug combination suppressed NF- κ B-mediated pro-inflammatory signalling pathways. Moreover, the combination treatment reduced activation of the c-JUN/JNK pathway, further improving the OA-like conditions in both goat and human ex vivo OA cartilage. Taken together, these results suggest that the combination of Dox and IGF-1 may represent a promising therapeutic approach for OA disease modification, thereby addressing a critical unmet need for improved treatment of OA.