Background: Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease affecting multiple joints and worsening the quality of life. Juglanin, a natural aldose reductase inhibitor, has shown to exhibit anti-inflammatory, anti-nociceptive, and anti-oxidant properties. Objective: The present study was undertaken to evaluate their possible mechanism of action against adjuvant-induced arthritis (AIA), i.e., Freund's complete adjuvant (FCA)-induced arthritis, in experimental rats. Materials and Methods: FCA (0.1 mL) was administered into the subplantar region of female Wistar rats paw to induced AIA. The rats were treated with vehicle (distilled water, 10 mL/kg) or leflunomide (10 mg/kg), or juglanin (10, 20, and 40 mg/kg, respectively) orally for the next 16 days. Various biochemical, molecular, and histological parameters were evaluated to determine the potential of juglanin. Results: Subplantar administration of FCA resulted in a statistically significant (P < 0.05) induction of AIA reflected by alteration in paw volume, joint diameter, paw withdrawal threshold, and paw withdrawal latency, which was statistically significantly inhibited (P < 0.05) by juglanin (20 and 40 mg/kg). It also statistically significantly attenuated (P < 0.05) FCA-induced elevated hepatic oxido-nitrosative stress and mRNA expressions of tumor necrosis factor-alpha (TNF-α), interleukin (IL) IL-1β, IL-6, transforming growth factor-beta (TGF-β), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOs). Western blot analysis revealed that juglanin statistically significantly downregulated (P < 0.05) protein expressions of NF-κB, IκBα, a disintegrin-like and metalloproteinase domain with thrombospondin-1 repeats (ADAMTS)-4, and ADAMTS-5 in hepatic tissue. It also statistically significantly attenuated (P < 0.05) histopathological anomalies induced in the tibiotarsal joint. Conclusion: The present communication suggests that juglanin attenuated altered mechano-tactile allodynia and hyperalgesia via inhibition of elevated oxido-nitrosative stress, cytokines (TNF-α and ILs) levels, immune-inflammatory (TGF-β, NF-κB, Ikβα, COX-2, and iNOs) mediators, and ADAMTS, thus exerting its anti-arthritic potential.