Valproate is a commonly used antiepileptic drug. Side effects from overdose or prolonged intake include the oxidation of neurons, hepatic steatosis and liver failure, as well as Fancony Syndrome. Extensive research has been done as to elucidate whether the adverse effects can be reduced by synergistic intake of natural bioactive molecules. C57Bl6 mice of both sexes were exposed for 10 days to individual and combined doses of 150 mg/kg valproate and 25 mg/kg naringin, a natural bioactive polyphenol from citrus plants. HepG2 and PK cells were also exposed in vitro. In the brain, liver and kidney, the valproate-induced, naringin-induced, and combination of these two compounds-induced lipid peroxidation (via malondialdehyde analysis, MDA), as well as the main markers of antioxidant cellular defense (superoxide dismutase-SOD, catalase-CAT, reduced glutathione-GSH) were compared in vivo and to the in vitro experiment. Additionally, transcription factors and enzymes of lipid metabolism (PPARα, PGC-1α, ACOX1, NFE2R2) and steatosis were analyzed in the liver. The aim was to determine whether the use of naringin reduces the side effects of valproate in vivo and in vitro experiments. The results were compared between the sexes as well. In the frontal and middle cerebral cortex, liver and kidney valproate caused lipid peroxidation. Naringin also caused lipid peroxidation but only in the brain and kidney, likely because of the pro-oxidant activity of catalytic doses of naringin in apolar environments. Naringin in combination with valproate did decrease damage to the liver and kidney, somewhat to the brain, and it did bring the levels of lipids and triglycerides, as well as the liver steatosis close to control levels. Naringin normalized the levels of PPARα and PGC-1α in the liver, and it brought the levels of acetyl CoA oxidase 1 (ACOX1) which valproate increases, close to control levels. A significantly higher oxidative stress was recorded in the male group, probably because of the antioxidant protection by estrogen afforded to females. The in vitro model could serve as a predictor of in vivo cellular responses, or as a replacement of in vivo models, although certain pretreatments with hormones and metabolites maybe necessary and should further be investigated.