Acute brain injury is a prominent admitting diagnosis of critically ill patients, often requiring endotracheal intubation to protect the airway and resulting in respiratory failure and the need for mechanical ventilation. Following brain injury, a primary focus is avoidance of secondary insults including both hypercarbia and hypoxemia. Hyperoxemia may also result in unanticipated neurologic consequences. Brain-lung crosstalk refers to complex relationships that drive iatrogenic injury in both organs, mediated by inflammation, immunosuppression, and autonomic dysfunction. In an effort to further reduce secondary brain injury, care must be taken from time of intubation to extubation to preserve cerebral blood flow and adequate oxygen delivery. This review describes timing and methodology for intubation of a patient with brain injury, the controversies and current recommendations related to mechanical ventilation settings, and the difficulty of decision-making with extubation and tracheostomy.