Oxidative stress leads to chondrocyte apoptosis and extracellular matrix (ECM) degradation, thus contributing to the pathogenesis of osteoarthritis (OA). Herein, curcumin with remarkable antioxidant and anti-inflammatory activities has been employed as an organic ligand to coordinate ferric ions for enhancing the water-solubility and biocompatibility of natural product curcumin. The obtained iron-curcumin-based coordination nanoparticles (Fe-Cur NPs) exhibit great water-solubility and efficient reactive oxygen/nitrogen species (ROS/RNS) scavenging ability. In vitro chondrocyte evaluation experiments indicated that the intracellular ROS/RNS induced by interleukin 1β (IL-1β) could be efficiently scavenged by these Fe-Cur NPs and oxidative-stress-induced cell death could be preserved as well. In addition, post intra-articular (i.a.) injection into OA rat joints, Fe-Cur NPs could greatly inhibit OA progression via activating the nuclear factor-erythroid 2 related factor-2 (Nrf2) and inhibiting nod-like receptor protein-3 (NLRP3) inflammasome activation in primary rat chondrocytes, as well as decrease the production of matrix degrading proteases and other inflammatory mediators. The efficient antioxidation and anti-inflammation performance of Fe-Cur NPs endow them as a promising nanoplatform for treatment of various inflammatory diseases, and more detailed researches will be conducted in the future.