This study evaluates the neurocognitive and electrophysiological effects of 1-year memantine treatment in 14 adolescents and young adults (mean age 24 years) with sickle cell disease (SCD, incluing sickle cell anaemia and sickle cell β-thalassemia), hypothesizing improvements in cognitive functions and neural processing. Participants underwent assessments using subtests from the Wechsler Intelligence Scale and a computerized task-switching paradigm with concurrent event-related potential (ERP) recordings, both before and after the treatment period. Assessments focused on processing speed, working memory, attention and executive function. ERP measurements targeted brain response changes during task switching. Memantine treatment enhanced cognitive test performance, especially in processing speed as shown by the Digit-Symbol Coding and Symbol-Search tests. Results indicated improved visuospatial and graphomotor speed, working memory and attention. The task-switching test revealed reduced error rates, suggesting decreased cognitive load and enhanced executive control. Electrophysiological changes in P1 and P3 amplitudes at frontal and parietal locations post-treatment pointed to more efficient neural processing in tasks requiring cognitive flexibility. These preliminary findings from a Phase II clinical study serve as a 'proof of concept', exploring the feasibility and potential effectiveness of memantine treatment in SCD-a previously uninvestigated context. They support the rationale for more extensive investigations to confirm these results and assess memantine's broader effectiveness.