Pathology of rheumatoid arthritis suggests autoimmunity linked to inflammation. This study is an attempt to identify targets of inflammation in joints and amelioration of the disease process by a natural product.Wistar rats were immunised with collagen, disease developed after 13±1 days post induction. Nigella sativa Linn. aqueous methanolic extract was given at two diffferent dosages, viz. 400 and 500 mg/kg daily until the 20th day. The analysis of inflammation and associated protease activation was evaluated by myeloperoxidase (MPO) and articular elastase (ELA). Post inflammatory generation of various free radicals was checked by evaluating several enzymatic and non enzymatic parameters (GSH, SOD and catalase), including peroxidation of membranes. Finally, articular nitrite content was estimated as to highlight the tissue injury evidenced by histology caused by autoimmunity.Nigella sativa decreased MPO and associated elastase activity dose dependently (p < 0.001). Moreover, Nigella sativa decreased the lipid peroxidation (p < 0.001) with replenishment of GSH (p < 0.001) confirming their inverse nature. SOD activity increased significantly (p < 0.01), with a parallel increment in catalase activity (p < 0.01). Consistent with these findings, articular nitrite content was reduced (p < 0.01), which was further confirmed by the histological findings. Our study suggests autoimmune stimulation of inflammatory cells and associated oxidative stress as a putative mechanism of RA and possible prevention by N. sativa.