Acute brain injury (ABI) affects up to one-third of patients using mechanical circulatory support (MCS). In venoarterial extracorporeal membrane oxygenation (VA ECMO), ABI incidence (11%–40%) has not improved in two decades. Conversely, improvements in left ventricular assist devices (LVADs) have reduced the incidence of stroke, although it remains a major complication (10%–30%). The failure of MCS to ensure adequate cerebral protection may impair cerebrovascular autoregulation (CVAR) and disrupt microcirculatory function affected by reduced pulsatility, endothelial injury, acute perturbations in partial pressure of arterial carbon dioxide (PaCO2), and cerebral venous congestion. Here, we review evidence demonstrating that these factors alter microcirculatory dynamics and CVAR, thereby contributing to ABI through shared mechanistic pathways. Current methods for assessing CVAR are reviewed, including invasive indices such as the pressure reactivity index (PRx) from intracranial pressure monitoring and noninvasive metrics such as the cerebral oximetry index (COx) from near-infrared spectroscopy or flow-velocity correlations from transcranial Doppler. Each method is limited by feasibility, signal artifacts, and inter-modality variability. Our review identifies three priority areas for cerebral protection in MCS: preservation of pulse pressure, cautious titration of PaCO2, and integration of CVAR-informed blood pressure management. Preliminary evidence suggests that very low pulse pressure, rapid carbon dioxide correction, and persistent microcirculatory impairment are each associated with ABI risk. Future investigations should focus on validating bedside tools to assess CVAR and microcirculatory integrity, and on determining whether physiological targets derived from these measures can improve neurological outcomes in patients using MCS.