Rheumatoid arthritis (RA) is a chronic progressive disabling autoimmune disease characterized by systemic inflammation of joints leading to damage of cartilage and bone around the joints. The adverse effects of many synthetic drugs, used as standard treatment for rheumatoid arthritis, compromise the therapeutic treatment. There is a prompt need for drugs with improved efficacy and safety profiles. The effect of Pseudobombax ellipticum (Kunth) Dugand leaves total extract and its fractions on complete Freund's adjuvant (CFA)-induced arthritis model in rats was investigated. Thirteen groups of 5 rats each were used. CFA-induced arthritis group was compared to 10 groups treated with the plant extracts relative to standard diclofenac treated group and normal control group. The plant extracts attenuated the increase in knee joint diameter and reversed the decrease in body weight as compared to CFA-injected rats. CFA-injected rats displayed a marked elevation in serum tumor necrosis factor (TNF)- α, interleukin (IL)-1β, prostaglandin (PG) E2, and nuclear factor kappa-Β (NF-kBp65), while rats treated with plant extracts displayed lowered serum levels of these pro-inflammatory cytokines. Also, the complete destruction and roughness of articular surface, shown in sections from CFA-injected rats, was markedly improved in sections from rats treated with the plant extracts. It is clear that, the picture of the disease was improved morphologically, biochemically and histologically by the plant extracts. Furthermore, 4 compounds were isolated for the first time with previously reported anti-inflammatory activity. These results may reveal the potential role for P. ellipticum (Kunth) Dugand leaves extracts as possible anti-inflammatory agent in rheumatoid arthritis management.