Background: Rheumatoid arthritis (RA) is a chronic, relapsing inflammatory and autoimmune multisystem disease that affects the joints. Methotrexate (MTX) is considered by many rheumatologists to be the most important and useful disease-modifying antirheumatic drugs (DMARDs). Fluoxetine is a selective serotonin reuptake inhibitor that has been widely used for the treatment of depression due to its safer profile. Moringa oleifera (MO) is known for its nutritional and medicinal uses. Various parts of these plant act as cardiac and circulatory stimulants. The present study was designed to evaluate the possible effect of methotrexate, Fluoxetine and Moringa Oleifera on rat model of RA. Materials and methods: Rats were classified into: Group I: control normal group. Group II: was not treated (diseased group). Group III: was treated with methotrexate (MTX) (0. 6 mg/kg/week/by oral gavage). Group IV: was treated with fluoxetine (20 mg/kg/day by oral gavage) Group V: was treated with Moringa Oleifera extract (200 mg/kg/day by oral gavage). Treated groups received drugs for 4 weeks. Results: Treated groups showed significant improvement in all parameters (rheumatoid factor (RF), tumor necrosis factor alpha (TNF-α), C-reactive protein (CRP), reduced glutathione (GSH), anti-cyclic citrullinated peptide (anti-CCP), arthritis score).and improvement of the histopathology of the joint. A significant reduction in the score was seen in the treated group at the end of 3rd and 4th weeks. With best results in Moringa Oleifera group in comparison with other treated groups. Conclusion: Methotrexate, fluoxetine and Moringa Oleifera extract groups showed significant improvement of parameters of RA.