Background and Objectives: The treatment of osteoarthritis (OA), a disabling degenerative disease, is clinically challenging due to the presence of inflammation at the damaged site and the poor self-healing capacity of the cartilage tissue. Intra-articular delivery of anti-inflammatory drugs such as celecoxib into damaged joints is more valuable than oral delivery due to rapid pain relief, high drug bioavailability, and reduced side effects. The biological properties of chitosan nanoparticles have led to their widespread applications in cosmetics, medicine, and pharmacy. Therefore, in this study, we aimed to improve the therapeutic efficacy of celecoxib, a lipophilic non-steroidal anti-inflammatory drug, through the formulation of drug-loaded chitosan nanoparticles.Materials and Methods: The nanoparticles were prepared by the ionic gel method, in which tripolyphosphate (TPP) was used as a cross-linker. After the synthesis of drug-loaded nanoparticles, the supernatant was collected to calculate the encapsulation efficiency and loading capacity. The formation of the nanoparticles was investigated by FTIR spectroscopy. The nanoparticle morphology, particle size distribution, zeta potential, and polydispersity index (PDI) were determined. The in vitro release of celecoxib from drug-loaded nanoparticles was evaluated at ۳۷ °C in PBS for ۷۲ h. MTT and hemolysis assays were performed to investigate the cytotoxicity and hemocompatibility of celecoxib-loaded nanoparticles, respectively.Findings: The formation of the nanoparticles was confirmed by FTIR spectroscopy. Nanoparticles showed an average size of ۳۵۲.۶ ± ۲۲.۵ nm and a zeta potential of + ۵۰.۴ ± ۱.۵ mV with drug loading and encapsulation efficiency of ۹۵.۸ ± ۰.۹% and ۵۴.۵ ± ۵.۲%, respectively. The images of AFM and SEM microscopies showed that the nanoparticles are spherical. The viability of chondrocytes was not affected by blank nanoparticles up to a concentration of ۱.۵ mg/ml. The hemolysis results showed that nanoparticles did not damage RBCs and had good hemocompatibility.Conclusions: Drug-loaded nanoparticles with homogeneous particle size, suitable drug loading capacity, and good hemocompatibility were successfully prepared for celecoxib delivery.