This study has aimed at utilization of novel and classical kidney function biomarkers to evaluate the nephroprotective potential of Carica papaya leaf extract (CPLE) in gentamicin nephrotoxicity model. The used classical biomarkers were urea and creatinine; while the new biomarkers were Kidney injury molecule-1 (KIM-1) and Clusterin. Forty-five male albino rats were assigned into 5 groups and subjected to different treatments for 9 consecutive days (vehicles; gentamicin, 100 mg/kg, subcutaneously; ascorbic acid, 200 mg/kg, orally; Carica papaya leaf extract, CPLE, 150 and 300 mg/kg b wt., orally). Three rats/group were sacrificed on days 3, 6 and 9 for blood and tissue samples. Gentamicin resulted in significant increase in urea and creatinine only by the end of the experimental course; while the novel biomarkers were evident as early as 3 days upon gentamicin injection. When concurrently administered with gentamicin, CPLE significantly ameliorated gentamicin nephrotoxic effects indicated by decrement of both the novel and the classical biomarkers, in a dose-dependent manner. CPLE-mediated protection was attributed to its antioxidant potential indicated by significant inhibition of malondialdehyde (MDA) levels in both serum and kidney homogenates. The results were further supported by histopathological examination that revealed considerable amelioration of the pathological microscopic alterations induced by repeated gentamicin injection. Phytochemical analysis of CPLE indicted presence of tannins and flavonoids. These data may suggest CPLE, based on improvement of both classical and novel renal markers, as a highly potent nephroprotective and antioxidant from natural source that could be a good remedy in conditions associated with renal disorders.