Lipids make up more than half of the human brain's dry weight, yet the composition and function of the brain lipidome is not well characterized. They not only provide the structural basis of cell membranes, but also take part in a wide variety of biochemical processes. In neurodegenerative diseases, lipids can facilitate neuroprotection and serve as diagnostic biomarkers. The study of organisms adapted to extreme environments may prove particularly valuable in understanding mechanisms that protect against stressful conditions and prevent neurodegeneration. The brain of the hooded seal (Cystophora cristata) exhibits a remarkable tolerance to low tissue oxygen levels (hypoxia). While neurons of most terrestrial mammals suffer irreversible damage after only short periods of hypoxia, in vitro experiments revealed that neurons of the hooded seal show prolonged functional integrity even in severe hypoxia. How the brain lipidome may contribute to the hypoxia tolerance of marine mammals has been poorly studied. We performed an untargeted lipidomics analysis, which revealed that lipid species are significantly modulated in marine mammals compared with non-diving mammals. Increased levels of sphingomyelin species may have important implications in efficient signal transduction in the seal brain. Substrate assays revealed elevated normoxic tissue levels of glucose and lactate, which may suggest an enhanced glycolytic capacity. Additionally, the neurotransmitters glutamate and glutamine were decreased, which may indicate decreased excitatory synaptic signaling in marine mammals. Analysis of hypoxia-exposed brain tissue suggests that these represent constitutive mechanisms rather than an induced response towards hypoxic conditions.