ObjectiveRepetitive head trauma is common in high‐contact sports. Cerebral blood flow (CBF) can measure changes in brain perfusion that could indicate injury. Longitudinal studies with a control group are necessary to account for interindividual and developmental effects. We investigated whether exposure to head impacts causes longitudinal CBF changes.MethodsWe prospectively studied 63 American football (high‐contact cohort) and 34 volleyball (low‐contact controls) male collegiate athletes, tracking CBF using 3D pseudocontinuous arterial spin labeling magnetic resonance imaging for up to 4 years. Regional relative CBF (rCBF, normalized to cerebellar CBF) was computed after co‐registering to T1‐weighted images. A linear mixed effects model assessed the relationship of rCBF to sport, time, and their interaction. Within football players, we modeled rCBF against position‐based head impact risk and baseline Standardized Concussion Assessment Tool score. Additionally, we evaluated early (1–5 days) and delayed (3–6 months) post‐concussion rCBF changes (in‐study concussion).ResultsSupratentorial gray matter rCBF declined in football compared with volleyball (sport‐time interaction p = 0.012), with a strong effect in the parietal lobe (p = 0.002). Football players with higher position‐based impact‐risk had lower occipital rCBF over time (interaction p = 0.005), whereas players with lower baseline Standardized Concussion Assessment Tool score (worse performance) had relatively decreased rCBF in the cingulate‐insula over time (interaction effect p = 0.007). Both cohorts showed a left–right rCBF asymmetry that decreased over time. Football players with an in‐study concussion showed an early increase in occipital lobe rCBF (p = 0.0166).InterpretationThese results suggest head impacts may result in an early increase in rCBF, but cumulatively a long‐term decrease in rCBF. ANN NEUROL 2023;94:457–469