Background and aim: Kidney stone disease (KSD) is considered one of the serious medical problems, despite recent management methods for kidney stones, there are many undesired consequences, thus recent literatures highlight the great need for natural compounds for safe, effective and affordable management of KSD. So, we aimed in this study to investigate the protective effect of Allium cepa administration against both stone formation process and its kidney injury effect. Hypothesis: Allium cepa administration has a beneficial role against renal stones formation and subsequent renal injury. Methods: 24 adult male albino rats were assigned into 3 groups; group I: control group; group II: received 0.75% ethylene glycol in the drinking water for 4 weeks; and group III received 0.75% EG in the drinking water plus freshly prepared Allium Cepa extract (ACE) 5ml/kg administration using intragastric tube for 4 weeks. The concentrations of creatinine and BUN in serum were measured, and urine analysis was done to assess creatinine clearance, proteinuria and kidney injury molecule-1 (KIM-1) levels. Tissue oxidative stress markers (SOD and MDA) were assessed, and kidney expression of SIRT-1, Beclin, LC3, osteopontin, and Regucalcin were measured by RT-qPCR. Histopathological assessment using Semi-thin Toluidine Blue Staining was done and immunohistochemistry for Bax, Beclin-1 and TNF-α markers was performed. Results: There was a significant increase of creatinine clearance value (P<0.05) with low serum creatinine and BUN levels in the ACE received group compared to EG group (P<0.001), in addition to decreased proteinuria and urine KIM levels in the ACE received group compared to EG group (P<0.001). The present study showed less stone formation, damage and apoptosis in the ACE received group compared to EG group (P<0.001). Moreover, the ACE received group showed significant lower expression of osteopontin and autophagy genes, but higher expression of regucalcin and SIRT-1 genes compared to the EG group (P<0.001). Regarding oxidative stress and inflammatory markers, MDA, TNF-α and mast cells filtration were significantly lower and SOD was significantly higher in the ACE received group than their levels in EG group (P<0.001). Conclusion: Alium Cepa extract administration has a significant protective effect against formation of renal stones and a great beneficial effect against renal injury in KSD. There were no external funding sources for this study, it is self-funding This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.