This study is an exploration of preclinical ef icacy and safety of Curcumin compared with conventional anti-inflammatory medication in the management of Rheumatoid Arthritis (RA) as a natural replacement. The models applied in Wistar rats were Collagen-Induced Arthritis (CIA) and Adjuvant-Induced Arthritis (AIA) after which the ef ects of Curcumin (200 mg/kg) were compared to Indomethacin (10 mg/kg). The measurement of parameters was done over 28 days: paw volume, arthritis score, body weight, and pain threshold with biochemical and histopathological parameters assessments. The ef ect of curcumin therapy on the treatment of arthritis showed a strong decrease in swelling, pain, inflammation of the joints, and the restoration of joint architecture and functions. Its anti-inflammatory and antioxidant ef ects were supported by serum cytokines (TNF- a, IL-1 b, IL-6) and markers of oxidative stress (MDA, GSH, and SOD). The histopathological analysis showed that the cartilage, as well as inflammatory infiltration, was preserved in the Curcumin-treated joints with minimal inflammatory infiltration. Notably, Curcumin did not exhibit any form of hepatic or gastrointestinal toxicity as opposed to the side ef ects of the normal NSAIDs. Altogether, Curcumin proved to be a powerful therapy with the ability to reduce RA symptoms, support functional performance, and increase the level of well-being. These findings aid the applicability of Curcumin as an adjunct/alternative and safe natural agent in the treatment of rheumatoid arthritis.