BACKGROUND: Rheumatoid arthritis (RA) is associated with joint damage. Effectiveness of embelin has been established in a wide variety of inflammatory disorders, but its utility as a therapeutic agent is limited by its poor absorption, rapid metabolism, and fast systemic elimination. To apprehend these limitations, we propose to use highly bioavailable embelin-loaded chitosan nanoparticles (CS-embelin NPs) for the treatment of RA. METHODS: The rats were made arthritic using a subcutaneous injection with 0.1 ml complete Freund's adjuvant (CFA) into the footpad of the left hind paw. CS-embelin NPs (25 and 50 mg/kg) was administered from day 15 to day 28 after adjuvant injection. After the experimental period, the animals were sacrificed and various biochemical markers were assessed. RESULTS: Arthritic score and paw swelling were significantly reduced after treatment with CS-embelin NPs. Arthritis-induced rats showed a significant increase in malondialdehyde (MDA) and nitric oxide (NO) with a concomitant reduction of antioxidants in the paw tissue. CS-embelin NPs (25 and 50 mg/kg) reduced MDA and NO levels and restored antioxidant levels to normalcy by mitigating oxidative stress. The arthritic rats exhibited elevated tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1beta (IL-1β) serum concentrations, upregulated TNF- α and IL-6 protein levels and upregulated nuclear factor-kB (NF-kB) mRNA expression in paw tissues. Treatment with CS-embelin NPs (25 and 50 mg/kg) significantly reduced serum levels and down-regulated inflammatory markers to normalcy, dose-dependently. CONCLUSION: The results suggest that CS-embelin NPs displayed a protective effect against adjuvant-induced arthritis in rats mediated through antioxidant and anti-inflammatory effects.