Purpose Ketogenic diet (KD) is recommended to avoid intense [18F]FDG myocardial physiologic uptake in PET imaging. Neuroprotective and anti-seizure effects of KD have been suggested, but their mechanisms remain to be elucidated. This [18F]FDG PET study aims to evaluate the effect of KD on glucose brain metabolism. Method Subjects who underwent KD prior to whole-body and brain [18F]FDG PET in our department for suspected endocarditis were retrospectively included. Myocardial glucose suppression (MGS) on whole-body PET was analysed. The main exclusion criteria were brain abnormalities. Thirty-four subjects with MGS were considered the KD population, and 14 subjects without MGS were considered a KD failure. Brain SUVmax of these groups was compared. Second, the KD population (n = 34, mean age: 61.8 ± 17.2 years) was compared to a control group of 27 healthy subjects fasting for at least 6 h (mean age of 62.4 ± 10.9 years). A semiquantitative voxel-based intergroup statistical analysis was conducted using SPM. Results A 20% lower brain SUVmax was found in subjects under KD with MGS in comparison to those without MGS, p = 0.02. Whole-brain voxel-based intergroup analysis revealed that patients under KD had relative hypermetabolism of limbic regions including medial temporal cortices and cerebellum lobes and relative hypometabolism of bilateral posterior regions (occipito-parietal). Conclusion KD globally reduces brain glucose metabolism but with regional differences. These results have a clinical implication, since the realization of a KD could lead to misinterpretation of these regions, and a pathophysiological perspective as it could help understand underlying neurological effects of KD through possible decrease of oxidative stress in posterior regions, and functional compensation in the limbic regions.