ABSTRACT Fipronil (FIP), a widely used agricultural insecticide, has raised significant concerns due to its harmful environmental residues and neurotoxic effects. Although FIP's toxicological impact has been studied in some neuronal cell models, its specific effects on human glial cells remain poorly understood. This study sought to investigate the mechanisms of FIP‐induced toxicity and evaluate the protective potential of vitamin E (VE), a known antioxidant. Using human astrocyte (GHA) cells, we treated cells with FIP (5–25 μM), VE (20 μM), or both and compared their responses to untreated controls. Our findings revealed that FIP significantly reduced cell viability and caused morphological changes in astrocytes, including cellular shrinkage and detachment. FIP also increased the production of reactive oxygen species (ROS) and depleted intracellular glutathione (GSH) levels, indicating a disruption of cellular redox balance and the onset of oxidative stress. Furthermore, FIP triggered the activation of apoptotic pathways through upregulation of Bax, caspase‐9, and caspase‐3, coupled with downregulation of the antiapoptotic protein Bcl‐2. Concurrently, FIP disrupted antioxidant defense mechanisms by modulating the Nrf2/HO‐1/NQO1 signaling pathway. Interestingly, pretreatment with VE effectively reversed these effects. VE reduced ROS levels, replenished GSH, mitigated apoptosis, and restored antioxidant protein expression, protecting astrocytes against FIP‐induced cytotoxicity and oxidative damage. These findings highlight oxidative stress as a critical factor in FIP‐induced astrocyte toxicity and position VE as a promising protective agent. Further research is essential to explore VE's therapeutic potential in mitigating oxidative stress‐related neurotoxicity caused by environmental toxins like FIP.