Extracorporeal life support (ECLS) is increasingly used to rescue patients with refractory respiratory failure, cardiogenic shock and/or cardiac arrest. Acute brain injury during ECLS is common and associated with a significant increase in mortality and long-term disability. Brain injury in ECLS patients can arise from either the underlying disease or pre-ECLS events, such as cardiac arrest, or from secondary mechanisms linked to ECLS-related complications, management strategies, and physiologic perturbations during support. In this review, we will focus on the modifiable factors and clinical management strategies to prevent or mitigate secondary brain injury during ECLS. Both veno-arterial membrane oxygenation (VA-ECMO) as well as veno-venous membrane oxygenation (VV-ECMO) will be discussed. First, we provide an overview of the interplay between patient and circuit related factors that determine brain perfusion and oxygen delivery in this critically ill patient population. Second, we highlight the importance of standardized multimodal neuromonitoring to detect evolving brain injury early and to guide individualized neurocritical care and ECLS management. Third, we identify modifiable ECLS factors and physiological targets which minimize secondary brain injury. We provide guidance on the titration of extracorporeal blood flow and blood pressure targets, the amount of sweep gas flow and oxygen fraction, temperature control and anticoagulation management. A comprehensive understanding of ECLS physiology and circuit–patient interactions, integrated with protocolized multimodal monitoring, enables individualized adjustment of modifiable ECLS settings to prevent or mitigate secondary brain injury.