Background: Rheumatoid arthritis is a chronic, common autoimmune disorder identified by progressive dysfunction of joints and cartilage damage. Oxypaeoniflorin (OPA), a Traditional Chinese Medicine monomer, has been reported for potential against inflammation and oxidative stress. Objectives: The objective of the study is to evaluate the potential of OPA against Freund complete adjuvant (FCA)-induced inflammatory pain in experimental arthritic rats. Materials and Methods: FCA was administered in female rats (Wistar strain) to induce polyarthritis, followed by 28 days of oral treatment with either vehicle, leflunomide (10 mg/Kg), or OPA (10, 20, and 40 mg/kg). Various parameters were assessed to determine the effect of OPA on pain and inflammatory pathway. Results: Adjuvant-induced arthritis (AIA)-induced elevated paw withdrawal latency and threshold suggested induction of arthritic pain. However, OPA (20 and 40 mg/kg) treatment diminished arthritic pain reflected by amelioration of hyperalgesia and allodynia. In addition, OPA showed an effective inhibition (P < 0.05) in FCA-induced alterations in alkaline phosphatase, alanine transaminase, aspartate aminotransferase, serum albumin, and C-reactive protein levels. The AIA-induced elevated oxido-nitrosative stress, protein levels of tumor necrosis factor-α, and interleukins in synovial tissue were effectively reduced (P < 0.05) by OPA. Moreover, OPA effectively downregulated (P < 0.05) enhanced nuclear factor-kappa beta (NF-κB), Ikβα, iNOs, and COX-2 mRNA expressions in synovial tissue. OPA also reduced histopathology alteration induced in the tibiotarsal joint by FCA. Conclusion: OPA exerts its antiarthritic property through inhibition of NF-κB/IκBα pathway to downregulate the activation of pro-inflammatory cytokines and inflammatory mediator thus, ameliorated arthritic inflammation and pain.