Background: Inflammation plays an important role in the progression of arthritis. The imbalance between pro-inflammatory and anti-inflammatory mediators regulates the induction and progression of arthritis. Nuclear factor kappa B (NF-kappa B) protein is ubiquitously present in all the cells. It controls the activation of immune system and regulates the inflammatory responses. Therefore, targeting NF-kappa B signaling pathway may be an effective strategy in treating arthritis. Neferine, a bisbenzylisoquinoline alkaloid, is present in the seeds of Nelumbo nucifera. Materials and Methods: In this study, arthritis was induced in rats with complete Freud's adjuvant (CFA, Group 2) and treated with neferine (Group 3) and diclofenac sodium (Group 4), respectively. The impact of neferine on arthritis was assessed by measuring the weight of organ, arthritis score index, hematological indices, and cytokines levels. Results: Hepatic enzymes were measured to assess the toxicity of neferine. The oxidative stress induced by CFA and the antioxidant property of neferine were estimated with biochemical assay, and their impact on the synovial tissue was confirmed with hematoxylin and eosin staining. To confirm the anti-inflammatory activity of neferine, the inflamed synovial tissue of normal and investigational animals was inspected through immunoblotting of NF-kappa B signaling proteins. Conclusion: Our overall results confirm that neferine effectively scavenged the oxidative stress induced by CFA and inhibited the NF-kappa B signaling, thereby alleviating the severity of arthritis. Histological analysis of the synovial tissue and arthritic score of arthritis-induced and neferine-treated rats authentically prove the potency of anti-arthritic drug in rat model.