Aluminum, one of the most abundant metallic elements, is known to be toxic to multiple organs including the kidneys. This study aimed to investigate the pleiotropic nephroprotective efects of Hesperidin in aluminum chloride (ALCL3)-induced renal injury, highlighting the potential molecular mechanisms underlying. Twenty-four male albino rats were divided into four groups: control, Hesperidin (80 mg/kg BW, orally), ALCL3 (10 mg/kg BW, IP), and ALCL3+Hesperidin groups. By the end of the study, blood samples were collected, and tissue samples were harvested at sacrifce. ALCL3 rats showed dramatically declined renal function, enhanced intrarenal oxidative stress, infammation, apoptosis, and extravagant renal histopathological damage with interstitial fbrosis as shown by a higher Endothelial, Glomerular, Tubular, and Interstitial (EGTI) score. Hesperidin signifcantly reversed all the aforementioned detrimental efects in ALCL3-treated rats. The study verifed the nephroprotective efects of Hesperidin on ALCL3-induced renal damage and confrmed the critical role of extracellular matrix (ECM) remodeling and apoptosis inhibition.