Purpose: Epilepsy is a widespread, long-term neurological condition triggered by an overabundance of electrical activity from the neurons in the brain. Genistein, a natural isoflavone found in soybeans, can prevent chronic diseases such as cardiovascular disease and osteoporosis. We aimed to investigate the potential protective effects of genistein on epilepsy using rat models through behavior analysis and investigation of key pathways, including antioxidant activity (Nrf2 and HO-1), promoting mitochondrial biogenesis (TFAM), and reducing brain tissue apoptosis (BCL2, BAX, and caspases). Main methods: PTZ was used to induce epilepsy in rats, and then they were treated with genistein. The hippocampus sections were stained with Nissl stain, and others were stained with anti-TFAM antibodies. Furthermore, TFAM, Nrf2, HO-1, BCL2, BAX, and caspases-3/8/9 gene expression and protein levels were quantified using quantitative real-time polymerase chain reaction (qRT-PCR) and complementary biochemical/functional assays. Results: Rats treated with genistein displayed notable progress in their behavior during behavioral tests. Sections stained with Nissl revealed that genistein increased the staining intensity of Nissl granules in the cerebral cortex. Additionally, genistein increased the expression of TFAM, Nrf2, HO-1, and BCL2, which reduced levels of BAX and caspase-3/8/9. Conclusions: Genistein safeguards against epilepsy in rats by enhancing their behavior and reinstating normal neuron structure. Its protective benefits may stem from its potential to boost antioxidant activity and promote mitochondrial biogenesis, which in turn decreases cell apoptosis.  Kulcsszavak: epilepsy, B-cell lymphoma 2 (BCL2), BCL2-associated X (BAX), heme Oxygenase-1 (HO-1), mitochondrial transcription factor A (TFAM), nuclear factor erythroid 2-related factor-2 (Nrf2)