Abstract Background: Rheumatoid arthritis (RA) is chronic irreversible inflammatory disorder and characterized by the thickening of synovial tissue with pannus formation and the destruction of joint structure; due to persistent overproduction of proinflammatory cytokines (TNF-α and IL-6), proinflammatory enzymes such as cyclooxygenase II (COX-2) and matrix metalloproteinases. Leflunomide, potent pyrimidine biosynthesis inhibitor, exhibiting anti-inflammatory and immunosuppressive actions and resveratrol is a potent antioxidant and anti-inflammatory agent; exerting potential antiarthritic effects and also can protect diverse tissue types as heart and colon in different experimental animal models. Objective: Evaluating outcomes of combinational use of both resveratrol and leflunomide on serum levels of proinflammatory biomarkers contributing to progression and severity of joint damage of adjuvant- induced arthritis in rats. Materials and Methods: 50 male Wistar rats divided into 5 equal groups, rheumatoid arthritis was induced by Complete Freund’s adjuvant. Arthritic rats were subdivided into 4 equal groups and taken the tested drugs daily for two weeks. Blood samples were taken for assay of serum levels of C-reactive protein, MDA, MMP-3, PGE2, IL-6, TNF-α and inflamed arthritic rat joints of hind paw from different rat groups were used for histological evaluation. Results: Arthritis rat group treated by concomitant resveratrol and leflunomide showed significant reduction in their serum levels C-reactive protein, MDA, MMP-3, PGE2, IL-6 , TNF-α, with histological improvement in comparison to others rat groups. Conclusion: Both drugs resveratrol and leflunomide exerted potent anti-inflammatory effects on serum levels of C-reactive protein, MDA, MMP-3, PGE2, IL-6, TNF-α and their concomitant use showed more significant ameliorative effects against joint damage reflected from histopathological analysis, with more additive inhibitory effects on serum levels of these cytokines and biomediators, that are strongly implicated in the pathogenesis and progression of RA and their combinational use is recommended for better management of RA in patients.