Human immunodeficiency virus (HIV) is a neurotropic virus that has a detrimental impact on the developing central nervous system (CNS) of children growing up with perinatal HIV (PHIV) due to a combination of pathophysiological processes related to direct viral cytopathic effects and immune activation. This leads to a spectrum of neurocognitive impairment ranging from severe encephalopathy to subtle domain-specific cognitive impairments, as well as psychological disorders that are compounded by HIV-related stigma and sociodemographic factors that disproportionately affect PHIV children. Early commencement and consistent use of combination antiretroviral therapy (cART) has resulted in a dramatic improvement in neuropsychological outcomes for PHIV children; however, they remain vulnerable to cognitive impairment and psychological disorders, as evidenced by imaging findings, randomised clinical trials and observational studies. An optimal neuroprotective cART regimen remains elusive in children, but systemic viral suppression, regular neurocognitive and psychological screening and ready access to neuropsychological management strategies are key components for optimising neuropsychological outcomes. However, a lack of standardised and validated screening tools, particularly in resource-limited settings, hinders a precise understanding of the nature, prevalence and associations between neuropsychological symptomatology and HIV health. This article reviews the natural history, cellular pathophysiology and structural and functional imaging findings for children growing up with HIV, as well as summarising management strategies related to antiretroviral therapy, screening tools and specific interventions for neurocognitive impairments and psychological disorders.