Obesity has become a global health issue, but effective therapies remain very limited. Adaptive thermogenesis promotes weight loss by dissipating energy in the form of heat, thereby representing a promising target to counteract obesity. Notably, the regulation of thermogenesis is tightly orchestrated by complex neuronal networks, especially those in the hypothalamus. Recent evidence highlights the importance of adenosine monophosphate-activated protein kinase (AMPK) within the ventromedial nucleus of the hypothalamus (VMH) in modulating thermogenesis. Various molecules, such as GLP-1, leptin, estradiol, and thyroid hormones, have been reported to act on the VMH to inhibit AMPK, which subsequently increases thermogenesis through the activation of the sympathetic nervous system (SNS). In this review, we summarize the critical role of AMPK within the VMH in the control of energy balance, focusing on its contribution to thermogenesis and the associated mechanisms.