The initial trauma to the brain that kills or damages nerve cells is only the first step in a drawn-out and complex cascade of events that cause further cell death. Immediately after a traumatic brain injury, cells at or close to the site of injury are mortally wounded, while others farther away from the injury are less-extensively wounded. However, within hours to days after the injury, if metabolic and cellular machinery in the nerves is too perturbed, the cells swell and die through necrosis. Necrosis can be caused by inflammatory factors produced in the brain, by free radicals entering into the brain, or by the excessive release of excitatory neurotransmitters, such as glutamate. Some cells that survive the initial injury may die days, weeks, or months later, when mechanisms inside the nucleus of the cell trigger a breakdown of its DNA. That process is known as apoptosis, or programmed cell death, because it is triggered by genes within the cell nucleus that respond to external signals caused by the injury.

Components of the secondary injury cascade include anoxia (absence of oxygen), hypoxemia (low oxygen content in the blood), hypotension (low blood pressure), anemia (low blood cell count), hemorrhage (bleeding in the brain), edema, and increased intracranial pressure. Edema is a common component of traumatic brain injury that occurs when disruption of the blood-brain barrier allows fluid to leak into the brain or when cellular swelling follows cell-membrane damage and ion-transport dysfunction. Edema increases intracranial pressure and can result in further damage to brain tissue. If intracranial pressure continues to increase, it leads to compression of the brain tissue and eventual herniation of tissue through the brain stem, resulting in death. In addition to edema, any new lesion or mass that occupies space causes increased intracranial pressure after traumatic brain injury, and if those masses continue to grow, permanent brain damage ensues.