AbstractAstroglia support neuron by providing substrates for neuronal metabolism, glutamate clearance, and antioxidative protection. Nuclear factor erythroid 2‐related factor 2 (Nrf2) participates in the antioxidative defense response. Also, Nrf2 signaling is recognized to activate the neurotrophic pathway to replace/protect damaged organelles. Ellagic acid (EA), an extraction component of fruits and nuts, presents many pharmacological activities such as anti‐inflammation, antioxidation, and neuroprotection. However, few studies have been focused on the neurotrophic properties of EA. Our study investigated whether EA could increase neuronal survival and the target cells. Thus, primary neuron‐enriched cultures and primary astroglia‐enriched cultures were applied to detect whether EA‐elicited neurotrophic effects were mediated by astroglia Nrf2. This study indicated that EA promoted neuronal survival. Further, astroglia Nrf2 participate in EA‐elicited neuronal survival with the following scenarios. First, EA elicited astroglia proliferation, glial cell line‐derived neurotrophic factor (GDNF) release, and Nrf2 activation. Second, after silencing astroglia Nrf2, EA‐induced astrogliosis, GDNF release, and neuronal survival disappeared. Thus, EA‐mediated astroglia Nrf2 activation is important to enhance neurotrophic effects on neurons, which might provide new insights for neurodegenerative disease.