Traumatic brain injury (TBI) involves an acute injury (primary damage), which may evolve in the hours to days after impact (secondary damage). Cortical spreading depolarization (CSD) is a metabolically demanding processes that may worsen the secondary brain injury. Metabolic stress has been associated with mitochondrial dysfunction, including impaired calcium homeostasis and elevated ROS production. However, the association between mitochondrial impairment and vascular function after TBI is poorly understood. We therefore aimed to 1) Identify the role of CSD on neurological outcome after TBI, 2) Measure changes of mitochondrial function after TBI and CSD and 3) Establish the effect of mitochondrial dysfunction on blood flow in the brain. For this, we used a rodent closed head injury model and found that CSD is associated with neurobehavioral decline after TBI. Craniotomy was performed to elicit CSD via electrical stimulation and we measured vascular dysfunction following CSDs in TBI animals using laser doppler flowmetry. We observed a more profound reduction in local cortical blood flow in TBI animals compared to healthy controls. CSD increased oxidative stress adjacent to the vasculature and using electron microscopy, we found that TBI and CSDs resulted in mitochondrial cristae damage in astrocytes, pericytes and endothelial cells. In healthy animals, stimulation of mitochondrial ROS production modulated cortical blood flow during CSD, similar to TBI animals. In contrast, inhibition of mitochondrial calcium uptake did not change blood flow. Overall, we provide evidence that CSDs induce mitochondrial dysfunction, impaired cortical blood flow, and neurobehavioral deficits in the setting of TBI.