Unilateral ureteral obstruction (UUO) is a well-established experimental model to evaluate renal interstitial fibrosis. Current study is aimed to investigate the effects of Nigella sativa (NS) extract and renin–angiotensin system (RAS) blockade against kidney damage following UUO in rats. In this study, the rats received intraperitoneal injection of losartan (15 mg/kg), captopril (30 mg/kg), and two doses of NS extract (200 and 400 mg/kg) for 18 consecutive days. At the fourth day of the experiment, laparotomy was performed, and the left ureter was ligated. Sham-operated animals received saline as vehicle, and laparotomy without ureteral ligation was done. UUO was associated with significant increase in the expression of renal angiotensin II and monocyte chemoattractant protein-1, concentration of malondialdehyde and tumor necrosis factor-α, and the number of apoptotic cells when compared with sham group. Renal total thiol content and the activity of antioxidant enzymes were significantly reduced as compared with the sham group. However, treatment of obstructed rats with losartan, captopril, and NS extract significantly improved these renal impairments when compared with UUO group. Thus, NS extract, a potent antioxidant and anti-inflammatory herb, is a therapeutic agent to treat the UUO-induced kidney damage comparable with the well-known RAS inhibitors captopril and losartan.