Omeprazole is used in acid-related gastrointestinal disorders but has prolonged usage adverse effects. The aim was to study changes in renal cortex following chronic Omeprazole administration and the possible protective role of ginseng. Rats were divided into control (C-), Ginseng (G-), omeprazole (OM-), and omeprazole-ginseng (OM-G) groups. Serum urea and creatinine levels and 24-hours urine-protein were determined. Kidneys were processed for histological study. Serum urea and creatinine and 24-hours protein were significantly higher in OM-group compared to controls and significantly decreased in OM-G group comparing to OM-group. OM-group showed significant glomerular and tubulointerstitial injury with vascular congestion, inflammatory cell infiltration, partial or complete damage of apical brush border of most tubules, interrupted basement membranes of glomerular capillaries and tubules, marked increase in collagen deposition, and significant increases in COX-2 and caspase-3 immune-expression. Co-administration of ginseng with omeprazole resulted in marked and significant improvement of these morphological changes. Conclusion: Omeprazole induced renal functional and morphological changes through inflammatory reaction, induction of fibrosis, cellular degeneration and apoptosis. Coadministration of ginseng ameliorated these effects through its anti-inflammatory, antifibrotic, and anti-apoptotic effects.