Neurotrauma, such as spinal cord injury and traumatic brain injury, often results in a break in a blood vessel and leads to a hemorrhagic stroke. Cells in the affected region of the brain often die because they no longer receive oxygen and nutrients from the blood and due to excessive glutamate concentrations, leading to the symptoms and disabilities of patients. Under such conditions, we have found that palmitoyl acyltransferase (PAT) zinc-finger DHHC containing 17 (zD17) directly interacts with c-Jun N terminus kinase (JNK), which promotes downstream neuronal cell death signals. We have developed a novel peptide (PP-002) targeting the JNK-interacting motif on zD17 to selectively block the enhancement of the zD17–JNK interaction and the activation of JNK isoforms 2 and 3. Application of PP-002 successfully blocks JNK activation and neuronal cell death pathways, protects cultured neurons from excitotoxicity, and dramatically reduces brain damage and behavioral deficits in a rat model of focal ischemic stroke.