Extracorporeal membrane oxygenation (ECMO) is a form of advanced cardiorespiratory support provided to critically ill patients with severe respiratory or cardiovascular failure. While children undergoing ECMO therapy have significant risk for neurological morbidity, currently there is a lack of reliable bedside tool to detect the neurologic events for patients on ECMO. This study assessed the feasibility of frequency-domain near-infrared spectroscopy (NIRS) for detection of intracranial complications during ECMO therapy. The frequency-domain NIRS device measured the absorption coefficient (µa) and reduced scattering coefficient (µs′) at six cranial positions from seven pediatric patients (0–16 years) during ECMO support and five healthy controls (2–14 years). Regional abnormalities in both absorption and scattering were identified among ECMO patients. A main finding in this study is that the abnormalities in scattering appear to be associated with lower-than-normal µs′ values in regional areas of the brain. Because light scattering originates from the intracellular structures (such as nuclei and mitochondria), a reduction in scattering primarily reflects loss or decreased density of the brain matter. The results from this study indicate a potential to use the frequency-domain NIRS as a safe and complementary technology for detection of intracranial complications during ECMO therapy.