Background Persea americana (PA) is a popular medicinal plant in folkloric medicines. The present study therefore investigates the ameliorative potentials of its leaves extract on carbon tetrachloride and rifampicin-induced toxicity in the liver, kidney and heart of albino rat. This was aimed at assessing the potentials of the plant in the management of liver, kidney and heart diseases. Methodology Forty (40) rats were randomly divided into eight (8) groups of five animals each. Groups I and II were administered with only distilled water and carbon tetrachloride (CCl4) respectively. Groups III and IV animals received 3.0 ml/kg bw of CCl4 and were treated with the extract at 50 mg/kg bw and 100 mg/kg respectively, while group V received 100 mg/kg bw. of silymarin orally for 14 days. Groups VI animals were administered with rifampicin (250 mg/kg bw.) only, while groups VII and VIII animals received rifampicin and were treated with 50 mg and 100 mg/kg bw of the extract respectively. Activities of creatine kinase, aspartate amino transferase, alanine amino transferase, alkaline phosphatase, superoxide dismutase, catalase as well as levels of urea, uric acid, bilirubin and malonidialdehyde (MDA) were assayed. Lipid profiles and histopathological examination of liver and kidney slices were also performed. Result Treatment with P. americana significantly (p < 0.05) restored all deranged biochemical parameters (creatine kinase, aspartate amino transferase, alanine amino transferase, alkaline phosphatase, urea, uric acid, bilirubin, MDA, lipid profile as well as superoxide dismutase and catalase) in a dose-dependent manner. Normal hepatic and renal histoarchitecture were also restored following treatment with P. americana. Conclusion Amelioration of distorted cardiac, hepatic and renal histoarchitecture as well as restoration of lipid profile, biomarkers of liver and kidney injury and antioxidant enzymes (catalase and superoxide dismutase) affirm the potential usefulness of P. americana in the management of liver, kidney and heart diseases.