BackgroundNeurological symptoms associated with coronavirus disease 2019 (COVID‐19), such as fatigue and smell/taste changes, persist beyond infection. However, little is known of brain physiology in the post‐COVID‐19 timeframe.PurposeTo determine whether adults who experienced flu‐like symptoms due to COVID‐19 would exhibit cerebral blood flow (CBF) alterations in the weeks/months beyond infection, relative to controls who experienced flu‐like symptoms but tested negative for COVID‐19.Study TypeProspective observational.PopulationA total of 39 adults who previously self‐isolated at home due to COVID‐19 (41.9 ± 12.6 years of age, 59% female, 116.5 ± 62.2 days since positive diagnosis) and 11 controls who experienced flu‐like symptoms but had a negative COVID‐19 diagnosis (41.5 ± 13.4 years of age, 55% female, 112.1 ± 59.5 since negative diagnosis).Field Strength and SequencesA 3.0 T; T1‐weighted magnetization‐prepared rapid gradient and echo‐planar turbo gradient‐spin echo arterial spin labeling sequences.AssessmentArterial spin labeling was used to estimate CBF. A self‐reported questionnaire assessed symptoms, including ongoing fatigue. CBF was compared between COVID‐19 and control groups and between those with (n = 11) and without self‐reported ongoing fatigue (n = 28) within the COVID‐19 group.Statistical TestsBetween‐group and within‐group comparisons of CBF were performed in a voxel‐wise manner, controlling for age and sex, at a family‐wise error rate of 0.05.ResultsRelative to controls, the COVID‐19 group exhibited significantly decreased CBF in subcortical regions including the thalamus, orbitofrontal cortex, and basal ganglia (maximum cluster size = 6012 voxels and maximum t‐statistic = 5.21). Within the COVID‐19 group, significant CBF differences in occipital and parietal regions were observed between those with and without self‐reported on‐going fatigue.Data ConclusionThese cross‐sectional data revealed regional CBF decreases in the COVID‐19 group, suggesting the relevance of brain physiology in the post‐COVID‐19 timeframe. This research may help elucidate the heterogeneous symptoms of the post‐COVID‐19 condition.Evidence Level2.Technical EfficacyStage 3.