Stroke is the 5th leading cause of death in the United States with no preventative therapies available. Compelling evidence suggests that mitochondria, a sub-cellular organelle important for cellular energy production, may provide a new therapeutic target. Inhibiting fission of mitochondria prevents brain damage during stroke however, the mechanism is poorly understood. Using in vivo mouse models we find that inhibiting mitochondrial fission improves mitochondrial bioenergetics preventing brain damage while promoting fission has the opposite effect.