Background: Kidneys exposure to toxins can cause injuries, leading to their functional impairments. Traditionally, plants have been used for the treatment of renal disorders and numerous medicinal plants have been tested for their nephroprotective effects, in such cases as gentamicin (GM) and cisplatin (Cisp)-induced nephrotoxicity. This study assessed the ability of Acalypha wilkesiana’s extract to counteract its toxic effect based on the biochemical, histological and proinflammatory cytokines components in rats. Methods: Thirty-six male Wistar rats were randomly divided into nine groups (n=4 each) and administered the following treatments: a) normal control (1 mL/kg body weight normal saline from days 1-10); b) nephrotoxin (GM 120 mg/kg, days 2-7; or Cisp 7 mg/kg on day 3); c) standard drug (120 mg/kg Silymarin plus GM or Cisp, days 1-10); and, d) extract groups (100 or 250 mg/kg, days 1-10 plus GM). Blood samples were collected and subjected to hematological and biochemical evaluations while kidney tissue samples were examined for histopathological alterations, pro- and antioxidants, and expression of pro-inflammatory cytokines. Results: Treatment of the rats pre-exposed to GM or Cisp with the extract decreased the serum creatinine, urea and MDA levels. The GST and GPx levels were also restored in rats. Glomerular atrophy with tubular epithelial necrosis induced by either nephrotoxin was restored to near normal. The expression of COX-2 following the administration of either nephrotoxin was reversed after treatment with the extract. Conclusion: The A. wilkesiana extract exhibited significant nephroprotective property, which could potentially be regarded as a promising alternative to the management of renal diseases.