We evaluated the functional brain activity in perinatally HIV-infected youth (PHIVY) on cART by quantifying the amplitude of low frequency fluctuations (ALFF) and correlated with clinical and cognitive measures. We observed higher neural activity for ALFF in PHIVY compared to control. ALFF values in the cerebral white matter were positively correlated with viral load. Higher neural activity was associated with poorer performance in psychomotor function, abstract thinking, and social cognition. The findings suggest that long-term consequence of higher neuroinflammation and associated neurorepair in PHIVY may have a significant impact on regional spontaneous neuronal firing consequently impacting neurodevelopment and cognitive functioning.