Objectives: Our study sought to evaluate the effects of silibinin in patients with active rheumatoid arthritis (RA) treated with methotrexate (MTX). Methods: We conducted a randomized multi-center, double-blind, placebo-controlled clinical trial over a 16-week treatment period at the Al-Sader and Baghdad Teaching Hospitals in Najaf and Baghdad, respectively. A total of 60 patients (30 of each sex) with active RA, already maintained on 12 mg MTX weekly for at least three consecutive months, were included in the study. Patients were randomly allocated to receive either 120 mg silibinin twice daily or a placebo, combined with their regular MTX regimen. The patients were evaluated by measuring disease activity score using the 28-joint Disease Activity Score, Simple Disease Activity Index, and Health Assessment Questionnaire–Disability Index scores at the start and end of the study. Blood samples were evaluated for the erythrocyte sedimentation rate (ESR), hemoglobin (Hb), high-sensitivity C-reactive protein (hs-CRP), creatine kinase (CK), anti-cyclic citrullinated peptide (CCP), and the serum cytokine levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, IL-10, and IL-2. Results: Silibinin significantly decreases the already elevated clinical scores compared to placebo treatment. ESR, IL-8, IL-6, TNF-α, anti-CCP, hs-CRP levels were significantly reduced. Additionally, the use of silibinin significantly increases Hb, IL-10, and IL-2 levels. Conclusion: Silibinin may improve the effects of MTX on certain biochemical and clinical markers of patients with active RA.