Traditional remedies for Moringa peregrina leaves have a variety of uses with confirmed biological and therapeutic effects, as per published reports. The current study aims to evaluate the ability of the leaves aqueous extract to protect from nephrotoxicity in gentamicin-treated mice. Phytochemical analysis for the aqueous extract was performed using DPPH (2,2-Diphenyl-1-picrylhydrazyl) assay for antioxidants, Folin-Ciocalteu, AlCl3 and HPLC- MS/MS analysis, focusing on phenol and flavonoid content. The nephroprotective activity of the prepared extract was evaluated by means of variable biochemical parameters including Creatinine (Cr), Uric Acid (UA), and Urea (Ur). In addition, histological examination of renal tissues was performed in all mice groups (control, gentamicin-induced (150 mg/Kg i.p) and aqueous extract-orally treated groups (500 and 1000 mg/Kg)). Findings reveal that the prepared extract has total phenols (555.57±0.92mg/g, equivalent to gallic acid), flavonoids (40.08±1.56 mg/g, equivalent to quercetin), and DPPH IC50 (3.10 µg/ml). HPLC-MS/MS analysis revealed the presence of 10 phenols and flavonoids compounds. In vivo studies showed a significant (P < 0.05) reducing effect for the high-dose treatment, on serum and urine concentrations for UA, Cr, and U, among the nephrotoxicity induced mice. Low-dose treated group showed significant reduction on serum concentration of UA, Cr and U, but only for Cr concentration in urine. The histological examination showed an improvement in the image of the renal tissue among the induced-nephrotoxicity mice, which was treated with high-dose extract. In conclusion, leaves aqueous extract of M. peregrina have shown potential protective effect to counteract some of the gentamicin consequences on kidney functions.