Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects the lining of the synovial joints and approximately affects 0.5-1% of the total population imposing a socioeconomic burden. Currently, there is no cure for RA, but receiving proper medical care at early stages of the disease is of high importance, to prevent the progressive disability and premature death. Using rat animal model injected with Complete Freund’s adjuvant proved to be successful in induction of a state highly resembling RA in human. Zinc oxide nanoparticles (ZnO NPs) are considered as one of the most important metal oxide nanoparticles due to their exclusive properties, and they are currently merged in several biological applications due to their biocompatibility, low cost, and high safety profile. In this study, we demonstrated the novel possible beneficial effects of using zinc oxide nanoparticles, on such devastating severe disease. Zinc oxide nanoparticles (ZnO NPs) proved to reduce the adjuvant-induced increased productions of IL-1β, TNF-α, IL-10, total leukocyte count, rheumatoid factor, anti-CCP levels in rats, suggesting an interesting option to be available either alone or in combinations to better control RA.In conclusion we recommend the expansion of more in vivo studies to highlight the benefits which could be obtained of nanoparticles either alone or in combination with the known anti-arthritic and/or anti-inflammatory agents; giving rise to new protocols to maximize the control of RA.