Medicinal potentials of Pergularia daemia leaves in managing hepato-renal toxicity induced by rifampicin were investigated. Twenty-five (25) Wistar rats were randomly placed into five groups containing five animals each. All the animals, except group I, were orally exposed to 250 g/kg bwt rifampicin and administered different treatments. Specific liver and kidney biomarkers such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were determined. In addition, malondialdehyde (MDA), lipid profile, superoxide dismutase (SOD), catalase (CAT), as well as reduced glutathione (GSH) were determined in the serum, liver, and kidney homogenates of experimental animals. Results indicate that exposure to rifampicin caused significant depletion in SOD and CAT relative to the control animals. Lipid profile was deranged, while ALT, AST, ALP, urea, uric acid, bilirubin, creatine kinase, and MDA level were elevated by rifampicin exposure. All deranged biochemical indices, as well as distorted histoarchitecture, were restored dose-dependently after treatment with P. daemia. In conclusion, P. daemia ameliorated rifampicin toxicity on the liver and kidney as indicated in the restoration of all deranged biochemical and histopathological indices measured. Hence, it is a potential therapeutic agent that can be harnessed as the panacea to the menace of liver and kidney diseases.