The use of extracorporeal membrane oxygenation (ECMO) has grown rapidly, driven by the COVID-19 pandemic. Despite its widespread adoption, neurological complications pose a significant risk, impacting both mortality and survivors' quality of life. Detecting these complications is challenging due to sedation and the heterogeneous nature of ECMO-associated neurological injury. Still, consensus of neurologic monitoring during ECMO is lacking since utilization and effectiveness of current neuromonitoring methods are limited. Especially in view of the heterogeneous nature of neurological injury during ECMO support an easily acquirable biomarker tracing neuronal damage independently from the underlying pathomechanism would be favorable. In a single-center prospective study on 34 severe acute respiratory distress syndrome (ARDS) patients undergoing ECMO, we explored the potential of serum neurofilament light chain levels (NfL) as a biomarker for neurological complications and its predictive power towards the overall outcome of ECMO patients. Individuals experiencing neurological complications (41%) demonstrated a notable rise in NfL levels (Tbaseline median 92.95 pg/ml; T24h median 132 pg/ml (IQR 88.6-924 pg/ml), p = 0.008; T7d median 248 pg/ml (IQR 157-1090 pg/ml), p = 0.001). Moreover, under ECMO therapy, these patients exhibited markedly elevated concentrations compared to those without neurological complications (T24h median 70.75 pg/ml (IQR 22.2-290 pg/ml), p = 0.023; T7d median 128 pg/ml (IQR 51.8-244 pg/ml), p = 0.002). There was no significant difference in the NfL dynamics between surviving patients and those who died during or shortly after ECMO therapy. While NfL indicates neuro-axonal damage during intensive care with ECMO therapy, we could not identify any correlation between survival outcome and the levels of NfL, indicating that NfL may not serve as a prognostic marker for survival. Nevertheless, additional studies involving a larger patient cohort are required.