Objective:This study aims to evaluate the efficacy and safety of Etanercept and Adalimumab in the treatment of polyarticular juvenile idiopathic arthritis (pJIA). Methods: From Jan 2021 to Oct 2023, 66 pJIA patients were prospectively randomized into Etanercept (n = 33) and Adalimumab (n = 33) groups at our hospital. Efficacy, via Juvenile Arthritis Disease Activity Score 10 (JADAS-10), and anti-cyclic citrullinated peptide (CCP), tumor necrosis factor-alpha (TNF-alpha), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), white blood cell count (WBC) were assessed pre-treatment and at 1-, 3-, 6-month intervals post-treatment. Adverse reactions were monitored. Results: Two groups showed comparable efficacy (P > 0.05) at baseline in anti-CCP, TNF-alpha, CRP, ESR, WBC, and JADAS-10 score. Treatment for a period of 1 to 3 months led to statistically significant reductions in these markers over time (P < 0.05). Adalimumab group was found significantly lower levels of mentioned markers than Etanercept group at 1-3 months (P < 0.05), but after 6 months, statistical differences vanished (P > 0.05). Normal total bilirubin, alanine transaminase, aspartate aminotransferase, serum creatinine levels were detected post-3 months in both groups; with similar adverse reaction rates (P > 0.05). Conclusion: Both Etanercept and Adalimumab are effective and safe for managing pJIA, demonstrating significant reductions in inflammatory markers and disease activity with no significant difference in efficacy or safety profiles. Clinical trial numberNot applicable.