Abstract: Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disorder characterized by persistent synovial inflammation, pannus formation, bone erosion, and eventual joint destruction. Murraya exotica L. (ME), a botanical source of Murrayae Folium et Cacumen (MFC), has not been previously investigated for its anti-arthritic potential, which motivated this study. The chemical composition of ME was characterized using ultra-performance liquid chromatography (UPLC), and its anti-arthritic effects were evaluated in collagen-induced arthritis (CIA) rats and interleukin (IL)-1β-stimulated SW982 cells. The contents of meranzin hydrate, hainanmurpanin, murrayone, and 3',4',5,5',6,7-hexamethoxyflavone in the ME extract were quantified as 2.86% ± 0.01%, 1.88% ± 0.01%, 0.07% ± 0.00%, and 0.01% ± 0.00%, respectively. In CIA rats, ME treatment alleviated clinical symptoms, attenuated histopathological joint damage, including synovial hyperplasia, cartilage degeneration, and bone erosion, ameliorated inflammation, and reduced oxidative stress. In IL-1β-stimulated SW982 cells, ME inhibited proliferation and migration, suppressed the inflammatory response, and mitigated oxidative stress. Network pharmacology and molecular docking analyses predicted strong interactions between ME-derived compounds (e.g., murrayone) and nuclear factor-kappa B (NF-κB) p65, which were further validated by cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) assay. Mechanistically, ME blocked NF-κB activation by inhibiting phosphorylation and degradation of inhibitor of NF-κB-α (IκBα) and preventing p65 nuclear translocation, while simultaneously suppressing activator protein-1 (AP-1) activation through downregulation of c-Fos and c-Jun. The involvement of the NF-κB and AP-1 pathways in ME-mediated anti-inflammatory, anti-proliferative, and anti-oxidative effects in RA was further confirmed using specific pharmacological inhibitors: pyrrolidinedithiocarbamate (PDTC) for NF-κB and SR11302 for AP-1.