Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disorder with massive suffering and permanent joint destruction. The Grape seed proanthocyanidin extract (GSPE) beneficial effects were evaluated in adjuvant-induced arthritis (AIA). RA was induced by 0.1 mL Freund's complete adjuvant (CFA) that was injected once into the rat's right hind leg footpads. Thirty male rats were equally divided into 5 groups. Group I (Normal control): Rats received no drugs, Group II (CFA- induced arthritis for treatment): Rats injected with 0.1 ml CFA on the 1st day and sacrificed after 29 days of CFA injection, Group III (CFA + GSPE treated): After 14 days of CFA injection, rats treated with GSPE (100 mg.kg-1 b wt./day) for 15 sequential days. Group IV (CFA- induced arthritis for protection): Rats injected with 0.1 ml CFA on 15th day of the experiment and sacrificed 15 days later after arthritis induction. Group V (CFA + GSPE protected): Rats pretreated with GSPE (100 mg.kg-1 b wt./day) one day before CFA injection and 14 days later after arthritis induction. A significant up-regulation in IL-1β, MMP‐3 and LOX-1 gene expressions were observed in the arthritic rats' synovial membrane. However, significant down-regulations in all previous parameters were observed in GSPE treated groups. Also, GSPE significantly activated Nrf2 gene in the liver with marked up-regulation of Lactoferrin (LF) gene in arthritic rats' synovial membrane. Interestingly, improvement of histopathological alterations in synovium and stifle joint capsule of arthritic rats supported the anti-arthritic effects of GSPE. Conclusively, GSPE ameliorates adjuvant induced arthritis via its anti-arthritic and joint protecting properties.