Amiodarone (AMD), an orally potent antidysrhythmic medication that has caused hepato-renal toxicity on long-term administration, is commonly used across the world. Zizyphus spina Christi leaves extract have ameliorative effects (ZSC). This research elucidated the magnitude of the damage to the liver and kidney tissues in AMD. Twenty four male albino rats were grouped into three groups given daily doses by gastric tube for two weeks as follows; the 1st group acted as a control group; the 2nd group received AMD; the 3rd group received AMD parallel to ZSC. Liver and kidney tissues prepared for histological examination and serum samples screened for biomarkers including; (I) liver injury enzymes: alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP); (II) kidney injury indicators: urea, creatinine and albumin; and (III) inflammatory markers: interleukins (IL-1α, IL-1β, IL-4, IL-6, IL-10, IFN-γ and IFN-α). The findings showed that AMD caused hepatic and renal histological changes that included congestion of the blood vessels, leucocytic infiltration, dilated bile ducts and lymphatics and cytoplasmic vacuolation were observed. The biochemical findings showed an increase in the AMD group’s ALT, AST, ALP, urea and creatinine levels in addition decrease in albumin concentration. The group of rats treated with AMD and ZSC, increased the improvements in liver and kidney histology, while the ALT, AST, ALP, urea and creatinine levels were reduced and albumin level increased and ameliorative the levels of inflammatory markers, interleukins. This finding collectively agreed that ZSC has a protective impact on AMD hepato-nephrotoxicity which can be due to its antioxidant properties.