Introduction: Chronic kidney disease is the progressive loss of renal function, measured by creatinine, urea and proteinuria levels. Literatures show that renal damages can be ameliorated naturally by medicinal plants, one such plant is Carica papaya . Fresh leaves of C. papaya were collected, powdered, and extracted with ethanol to form ethanolic extract of C. papaya leaves (ECP). Aim and Objectives: The aim and objective of this study are to assess the remedial implications of ethanolic ECP leaves on mercuric chloride (HgCl2)-induced nephrotoxicity in female Wistar rats. The objectives of this study were to assess the effectiveness of two different oral doses of ECP using immunohistochemistry, histopathology, and serum biomarkers such as kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, and semaphorin 3A. Materials and Methods: The rats were divided into five groups (n = 6): Control (Physiological saline, 2 ml/kg b. w), Negative control (HgCl2, 2.5 mg/kg b. w), Positive control (N-acetyl cysteine [NAC] 180 mg/kg b. w + HgCl2, 2.5 mg/kg b. w), Experimental group (C. papaya leaves, 300 and 600 mg/kg b. w + HgCl2, 2.5 mg/kg b. w) for 28 days orally through gavage. Collection of blood and renal tissue was done to determine the serum biomarkers, immunohistochemistry, and histopathology. Results: Pretreatment with 300 mg and 600 mg doses of ECP had protective effects slightly lower than NAC and equal to that of NAC on HgCl2-induced nephrotoxicity, respectively. Statistical analysis was performed using the one-way analysis of variance using SPSS version 17.0 with a statistical significance level of P < 0.001. Such pretreatment of C. papaya leaves, modified the following; (a) levels of serum marker enzymes (b) histopathological changes, and (c) immunohistochemistry expression caused by HgCl2. Conclusion: ECP plays a very significant role in the management of nephrotoxicity induced by HgCl2with equivalent to NAC.