Background and objective: Youth with sickle cell disease (SCD) without neurological complications continue to be at increased risk of neurocognitive difficulties. Nocturnal hypoxemia is associated with neurocognitive outcomes and has been identified as a chronic complication in youth with SCD. The objective of this study was to assess the relationship between sleep disturbances and neurocognitive functioning in youth with SCD, while taking into account demographic and socioeconomic factors. Methods: Youth with SCD were identified through retrospective chart review who underwent a standardized polysomnography (PSG) and completed a neuropsychological testing battery to assess cognitive skills, including verbal comprehension, working memory, processing speed, and cognitive flexibility. Questionnaires were also collected to assess parent-reported concerns with their youth's executive and adaptive skills. Results: Twenty-seven youth with SCD, ages 6–17, were identified who completed both a PSG and neuropsychological testing. Results demonstrated that verbal comprehension decreased by 2.37 standard points for every unit decrease in mean nocturnal oxygen saturation (SpO2) (p = 0.031). Working memory was also found to decrease by 1.46 standard points for each 1% increase in time spent under 90% oxygen saturation (pTST SpO2 < 90%) (p = 0.030). Sleep parameters did not significantly predict other cognitive scores or parent-reported executive or behavioral ratings. Conclusion: Our study found that sleep disturbance, mean nocturnal SpO2 and pTST SpO2 < 90%, significantly affected verbal comprehension and working memory performance, respectively. Overall, these findings have the potential to identify sleep needs in youth with SCD to promote sleep-targeted interventions as a modifiable factor to reduce neurocognitive deficits.