Managing children with critical neurological conditions requires a comprehensive understanding of several principles of critical care. Providing a holistic approach that addresses not only the acute interactions between the brain and different organ systems, but also critical illness-associated complications and recovery is essential for improving outcomes in these patients. The brain reacts to an insult with autonomic responses designed to optimize cardiac output and perfusion, which can paradoxically be detrimental. Managing neuro-cardiac interactions therefore requires balancing adequate cerebral perfusion and minimizing complications. The need for intubation and airway protection in patients with acute encephalopathy should be individualized following careful risk/benefit deliberations. Ventilatory strategies can have profound impact on cerebral perfusion. Therefore, understanding neuro-pulmonary interactions is vital to optimize ventilation and oxygenation to support a healing brain. Gastrointestinal dysfunction is common and often complicates the care of patients with critical neurological conditions. Kidney function, along with fluid status and electrolyte derangements, should also be carefully managed in the acutely injured brain. While in the pediatric intensive care unit, prevention of critical illness-associated complications such as healthcare-associated infections and deep vein thrombosis is vital in improving outcomes. As the brain emerges from the acute injury, rehabilitation and management of delirium and paroxysmal sympathetic hyperactivity is paramount for optimal recovery. All these considerations provide a foundation for the care of pediatric patients with critical neurological conditions in the intensive care unit.