Background: Some of the major complications of sickle cell disease (SCD) occur in the brain and apart from overt stroke, patients also present with cognitive impairments. We sought to evaluate the prevalence of cognitive deficits as well as their biological predicting factors in young SCD patients in Cameroon. Methods: The cognitive performances of Cameroonian SCD young patients were evaluated using a neuropsychological test battery assessing four domains of cognitive functioning (executive functions, attention, memory, and sensory-motor skills) previously adapted and normalized on healthy subjects in Yaoundé. Findings: Up to 37.5% of the 96 SCD patients aged 6 to 24 years (M = 13.5, SD = 4.9) had mild-tosevere cognitive deficits. The cognitive deficits tend to increase with age. There was a significant effect of SCD on executive functions and attention, whereas SCD patients performed as well as controls on memory and sensory-motor skills tests. Structural equation models showed a significant association between (a) severe anemia and lower executive functioning, (b) low fetal hemoglobin levels and lower executive functioning and attention, (c) history of cerebrovascular accidents and lower performances in executive functioning, sensory-motor skills, and memory, (d) pathological electroencephalogram and lower attention, and (e) abnormal Transcranial Doppler and lower memory. Conclusion: SCD patients in Cameroon presented a very high prevalence of cognitive deficits, with a specific impairment of executive functions and attention. Routine neuropsychological evaluation for early detection of cognitive deficits in SCD patients could represent a cost-effective tool to implement in resource-limited contexts such as in sub-Saharan Africa.