Background Excessive reactive oxygen species (ROS) is produced by Ischemia-reperfusion (IR) injury that results in serious neurological disruption. Even though many antioxidant drugs can scavenge ROS, there has not been a sustainable drug for brain IR injury due to the limitation of blood-brain barrier (BBB) penetration, insufficient drug efficiency, unexpected side effects. Nanomaterials can improve these problems by delivering organic drugs, but the release of environmental hazards is still a concern. Results We used a simple one-pot synthesis method for the fabrication of IR-targeted nanomedicine, i.e., D-glutathione stabilized gold nanoclusters (GSH-AuNCs) for the treatment of brain IR injury. Though no additional drug was delivered, GSH-AuNCs themselves were found to penetrate BBB, suppressing ROS and neuroinflammation. GSH-AuNCs also exhibited excellent renal clearance efficiency due to the ultra-small sizes. This drug neither remains in the body nor pollutes the environment. Conclusion With high clearance ability, insignificant environmental concerns, GSH-AuNCs are promising for treating IR injury and can be used as a sustainable drug for practical applications.