OBJECTIVE: We investigated the mechanism of histone deacetylase 2 (HDAC2) modulating nuclear factor erythroid 2-related factor 2 (Nrf2) acetylation level in neuronal ferroptosis of hypoxic-ischemic brain injury (HIBI) neonatal rats. METHODS: The pathological damage and neuronal injury in the hippocampal CA1 region of HIBI neonatal rat models were assessed by HE and Nissl staining. Levels of neuron-specific enolase (NSE), glutathione peroxidase 4 (GPX4), HDAC2, Nrf2, glutathione (GSH), reactive oxygen species (ROS), malondialdehyde (MDA), active Fe RESULTS: HIBI induced upregulation of HDAC2 expression, causing hippocampal neuronal ferroptosis in neonatal rats, as evidenced by dissolved hippocampal CA1 region, neuronatrophy, reduced number of neurons, abated NSE and GPX4 levels, decreased NeuN+/GPX4+ cells, diminished GSH level, and increased levels of ROS, MDA and active Fe CONCLUSION: HDAC2 modulated neuronal ferroptosis in HIBI neonatal rats by mediating Nrf2 deacetylation.