Neuron-specific enolase (NSE) is a marker used to assess neurological impairment. Notwithstanding, the release of NSE into the circulation can also originate from erythrocytes and thrombocytes, signifying that even mild instances of hemolysis have the potential to induce heightened serum NSE levels. The present study addresses the question of whether the serum NSE level is a reliable parameter for assessing potential brain damage in patients undergoing extracorporeal membrane oxygenation (ECMO). To this end, NSE values of all non-resuscitated ECMO patients treated at our clinic from January 2020 to March 2022 were retrospectively evaluated. Serum NSE levels were found to be median 35.95 µg/L, with significant intrapersonal variability during ECMO therapy. A comparative analysis in ECMO patients with and without diagnosed brain damage revealed no statistically significant differences. In contrast, the concurrent measurement of serum LDH and NSE levels exhibited a significant positive correlation (Spearman Rho 0.69), indicating that the elevated serum NSE levels exhibited by patients devoid of cerebral impairment were attributable to the occurrence of ECMO-induced hemolysis. Consequently, the prognostic value of serum NSE levels in patients undergoing ECMO is restricted. The data also demonstrate that individual measurements of serum NSE levels in ECMO patients should be regarded as snapshots with only limited significance.