Individuals with Prader-Willi syndrome (PWS) display developmental delays, cognitive impairment, excessive hunger, obesity, and various behavioral abnormalities. Current PWS treatments are limited to strict supervision of food intake and growth hormone therapy, highlighting the need for new therapeutic strategies. Brain-derived neurotrophic factor (BDNF) functions downstream of hypothalamic feeding circuitry and has roles in energy homeostasis and behavior. In this preclinical study, we assessed the translational potential of hypothalamic adeno-associated virus (AAV)-BDNF gene therapy as a therapeutic for metabolic dysfunction in the Magel2-null mouse model of PWS. To facilitate clinical translation, our BDNF vector included an autoregulatory element allowing for transgene titration in response to the host’s physiological needs. Hypothalamic BDNF gene transfer prevented weight gain, decreased fat mass, increased lean mass, and increased relative energy expenditure in female Magel2-null mice. Moreover, BDNF gene therapy improved glucose metabolism, insulin sensitivity, and circulating adipokine levels. Metabolic improvements were maintained through 23 weeks with no adverse behavioral effects, indicating high levels of efficacy and safety. Male Magel2-null mice also responded positively to BDNF gene therapy, displaying improved body composition, insulin sensitivity, and glucose metabolism. Together, these data suggest that regulating hypothalamic BDNF could be effective in the treatment of PWS-related metabolic abnormalities.