We identified the FoxO3a activator trifluoperazine (TFP), a FDA-approved antipsychotic agent that reduced ferroptosis-associated brain ischemia/reperfusion (CIR) injury in rats through AMPK/FoxO3a/HIF-1α/SLC7A11 signaling and mitochondria-dependent mechanisms. Here, FOXO3 is linked to brain ischemia.