Rheumatoid arthritis (RA), autoimmune disease that is categorized via chronic inflammation manifestation, obesity, cardiovascular risk and even enhanced the mortality and affect the 0.3 and 1% of population worldwide. The current experimental study was scrutinize the anti-arthritic effect of b-sitosterol loaded solid lipid nanoparticles (SLN) against complete Fruend adjuvant (CFA)-induced arthritis via dual pathway. Double emulsion solvent displacement method was used for the preparation of b-sitosterol solid lipid nanoparticles (SLN). CFA was used to induce arthritis and rats were divided into different groups for 28 days. Biochemical, anti-inflammatory, pro-inflammatory cytokines and inflammatory mediator were estimated, respectively. Receptor activator of nuclear factor kappa-B ligand (RANKL), signal transducer and activator of transcription-3 (STAT3) nuclear factor erythroid 2-related factor 2 (Nrf 2), Heme Oxygenase-1(HO-1) and Nuclear factor-jB (NF-jB) expression were estimated. b-sitosterol-SLN significantly (p < .001) reduced the paw edema, arthritic index and increased the body weight. b-sitosterol-SLN increased the redox status of synovium freduce the malonaldehyde (MDA) and increase superoxide dismutase (SOD), glutathione (GSH) and catalase (CAT)g level and reduced the cytokines such as tumor necrosis factor-a (TNF-a), interleukin-1b (IL-1b), interleukin-2, interleukin-6, interleukin-16, interleukin-17 and increased level of interleukin-10, Transforming growth factor beta (TGF-b). b-sitosterol-SLN significantly (p < .001) reduced the level of cyclooxygenase-2 (COX-2), prostaglandin E 2 (PGE 2), vascular Endothelial Growth Factor (VEGF) and NF-jB. b-sitosterol-SLN significantly increased the expression of HO-1,Nrf 2 and decreased the expression of NF-jB, RANKL, STAT3. In conclusion, b-sitosterol SLN showed the antiarthritic effect via suppression of NF-kB and activation of HO-1/Nrf-2 pathway.