Most patients with COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), display neurological symptoms, and respiratory failure in certain cases could be of extra-pulmonary origin. With reports detecting SARS-CoV-2 in some post-mortem patient brains, the routes, targets and consequences of brain infection merit investigation. Hypothalamic neural circuits play key roles in sex differences, diabetes, hypertension, obesity and aging, all risk factors for severe COVID-19, besides being connected to brainstem cardiorespiratory centers. Here, human brain gene-expression analyses reveal that the hypothalamus and associated regions express angiotensin-converting enzyme 2 and transmembrane proteinase, serine 2, which mediate SARS-CoV-2 cellular entry, in correlation with several genes or pathways involved in physiological functions or viral pathogenesis. Immunolabeling in human and animal brains suggests that the hypothalamus could be central to SARS-CoV-2 brain invasion through multiple routes, and that sex hormones and metabolic diseases influence brain susceptibility.