Optimizing mechanical ventilation in patients with acute brain injury (ABI) presents a complex clinical challenge, requiring a delicate balance between minimizing secondary cerebral injury and preventing ventilator-induced lung injury (VILI). The intricate interplay between respiratory and cerebral physiology mandates an individualized approach to ventilatory management. Core goals include maintaining normoxia and normocapnia to avert cerebral ischemia from hypoxia or hypocapnia while avoiding intracranial hypertension associated with hypercapnia. However, evidence guiding the ideal tidal volume and positive end-expiratory pressure (PEEP) settings in this population remains limited, particularly regarding their impact on cerebral perfusion pressure and oxygen delivery. Advanced neuromonitoring modalities-such as transcranial Doppler ultrasound and brain tissue oxygen tension (PbtO₂) monitoring-offer critical real-time data to inform ventilation strategies. Additionally, emerging technologies, including automated and adaptive modes of ventilation, show promise in enhancing patient-ventilator synchrony and gas exchange. This narrative review synthesizes current physiological principles, discusses the challenges inherent in protecting both the brain and lungs, and explores the evolving role of precision ventilation strategies supported by multimodal monitoring. Integrating these approaches may improve neurological and respiratory outcomes and help close the evidence gaps in ABI management.