Energy balance is regulated by several hormones and peptides, and neuropeptide Y is one of the most crucial in feeding and energy expenditure control. NPY is regulated by a series of peripheral nervous and humoral signals that are responsive to nutrient sensing, but its role in the energy balance is also intricately related to the energetic status, namely mitochondrial function. During fasting, mitochondrial dynamics and activity are activated in orexigenic neurons, increasing the levels of neuropeptide Y. By acting on the sympathetic nervous system, neuropeptide Y modulates thermogenesis and lipolysis, while in the peripheral sites, it triggers adipogenesis and lipogenesis instead. Moreover, both central and peripheral neuropeptide Y reduces mitochondrial activity by decreasing oxidative phosphorylation proteins and other mediators important to the uptake of fatty acids into the mitochondrial matrix, inhibiting lipid oxidation and energy expenditure. Dysregulation of the neuropeptide Y system, as occurs in metabolic diseases like obesity, may lead to mitochondrial dysfunction and, consequently, to oxidative stress and to the white adipose tissue inflammatory environment, contributing to the development of a metabolically unhealthy profile. This review focuses on the interconnection between mitochondrial function and dynamics with central and peripheral neuropeptide Y actions and discusses possible therapeutical modulations of the neuropeptide Y system as an anti-obesity tool.