Background: Esomeprazole is one of the proton pump inhibitors used in the treatment of gastrointestinal disorders. In spite of its safety, it can induce many side effects, especially acute interstitial nephritis that may progress into acute renal failure. Aim: This work aimed to investigate the effect of proton pump inhibitor (esomeprazole) on the histological structure of the renal cortex of adult male albino rats, as well as the effect of stoppage of that exposure. Materials and methods: 30 adult male albino rats were divided into three groups (10 rats each); control, esomeprazole group: rats received 5 mg/kg/day esomeprazole orally for 4weeks, and recovery group by which rats received esomeprazole 5 mg/kg /day orally, then left for another 4 weeks without treatment. After that, the renal cortex obtained and processed for light and transmission electron microscopic examination. Results: Esomeprazole group showed shrunken glomeruli with widening of Bowman's space, vacuolated glomerular and tubular cells, with darkly stained nuclei, focal interruption of PAS reaction in the brush border of PCTs besides statistically significant decrease in the mean optical density for PAS when compared with control, and focal ultrastructural changes in renal corpuscles, proximal and distal convoluted tubules. In recovery group; partial improvement of the previous histopathological findings observed. Conclusion: Esomeprazole induced histopathological changes in the structure of the renal cortex of adult male albino rats, which could be partially improved if left to recover.