Phenytoin (PHT) is one of the most used anticonvulsants in the developing world, but lack of monitoring and concurrent medications can easily cause harmful negative effects on the liver and kidneys. Herbal medicines have consistently drawn the interest of researchers in contrast to drug therapies, which have a number of negative effects. The current study looked into the protecting impacts of Thuja occidentalis (TO) against phenytoin-exposed rats’ hepatic and renal damage. In the current work, young, non-woody Thuja occidentalis L. was extracted using a newly made methanolic solution. This study used distillation-based methods to obtain branches with leaves. The study involved of three groups of eight rats per group. Group I rats acted as a control group, whereas group II take 75 mg/kg of PHT alone. Groups III received PHT parallel to TO 200 mg/kg for 14 consecutive days. Liver and kidney tissues prepared for histological examination and serum samples separated for biomarkers. (I) liver injury indicator enzymes, alanine aminotransferase ALT, aspartate aminotransferase AST and alkaline phosphatase ALP; (II) kidney injury indicators as urea and creatinine. (III) inflammatory markers, interleukins (IL-1α, IL-1β, IL-4, IL-6, IL-10, IFN-γ and IFN-α) were subsequently determined. The findings showed that PHT exposure group elicited significant increases (p < 0.05) in ALT, AST, ALP, urea and creatinine levels. Moreover, some hepatic and renal histological changes were observed. However, rats co-treated with TO, had their functional indices of the liver and kidneys returned to nearly normal levels. In conclusion, Thuja occidentalis might guard the liver and kidneys from damage brought on by PHT medication.