In addition to their prominent roles in the control of reproduction, estrogens are important modulators of energy balance, as evident in conditions of deficiency of estrogens, which are characterized by increased feeding and decreased energy expenditure, leading to obesity. AMP-activated protein kinase (AMPK) is a ubiquitous cellular energy gauge that is activated under conditions of low energy, increasing energy production and reducing energy wasting. Centrally, the AMPK pathway is a canonical route regulating energy homeostasis, by integrating peripheral signals, such as hormones and metabolites, with neuronal networks. As a result of those actions, hypothalamic AMPK modulates feeding, as well as brown adipose tissue (BAT) thermogenesis and browning of white adipose tissue (WAT). Here, we will review the central actions of estrogens on energy balance, with particular focus on hypothalamic AMPK. The relevance of this interaction is noteworthy, because some agents with known actions on metabolic homeostasis, such as nicotine, metformin, liraglutide, olanzapine and also natural molecules, such as resveratrol and flavonoids, exert their actions by modulating AMPK. This evidence highlights the possibility that hypothalamic AMPK might be a potential target for the treatment of obesity.