In human preterm newborns, caffeine increases brain activity and improves neurodevelopmental outcomes. In animal models of hypoxic ischemic brain injury, caffeine pretreatment reduces infarct volume. We studied the relationship between tissue neuroprotection and brain activity after injury to further understand caffeine neuroprotection. Rat dams received caffeine prior to birth or on postnatal day 3 (P3) through P16. Caffeine-treated and -untreated pups underwent the Vannucci procedure (unilateral carotid ligation, global hypoxia) on P2. A subset had EEG recordings. Brain hemispheric infarct volume was measured on P16. P2 hypoxic ischemia (HI) results in histologic brain injury (mean ± standard deviation infarct volume 10.3 ± 4.6%) and transient suppression of EEG activity. Caffeine pretreatment reduces brain injury (mean ± standard deviation infarct volume 1.6 ± 4.5%, p < 0.001) and improves amplitude-integrated EEG (aEEG) and EEG burst duration and amplitude. Caffeine treatment after HI does not reduce infarct volume (mean ± standard deviation 8.3 ± 4.1%, p = 1.0). However, caffeine posttreatment was equally effective at restoring aEEG amplitude and EEG burst duration and amplitude. Thus, caffeine supports brain background electrical activity independent of tissue neuroprotection.© 2020 S. Karger AG, Basel.