In the therapy of rheumatoid arthritis, ibuprofen (IBU) is widely used; however, it has been limited the clinical use by its systemic side effect, such as gastrointestinal lesions. Therefore, we prepared topical gel ointment used IBU solid nanoparticles (IBU_nano-gel formulation). In addition, we demonstrated their anti-inflammatory effect by using arthritis model rat (adjuvant-induced arthritis rat, AA rat). The gel formulations were prepared using additives (Carbopol 934, 2-hydroxypropyl-β-cyclodextrin and methylcellulose) and bead mill-method. The IBU particle size in the IBU_nano-gel formulation was 208 nm. The increase in inflammation of the hind feet of AA rats was attenuated by the treatment with the IBU_nano-gel formulation, and preventive effect was higher than that of a gel formulation containing IBUmicroparticles (IBU_micro-gel formulation, mean particle size 85.4 μm); the accumulation and permeability through the skin of IBU from the IBU_nano-gel formulation were significantly larger in comparison with the IBU_micro-gel formulation. Further, no gastrointestinal lesions were observed in AA rats following the repetitive administration of the 5% IBU_nano-gel formulation (0.30 g) for 42 days (once a day). These results suggest that the dermal application of IBU-nanoparticles provide effective and efficient therapy that spares patients from unwanted side effects.