Besides its quintessential role in reproduction, 17β-estradiol (E2) is a potent anorexigenic hormone. E2 and the selective Gq-coupled membrane estrogen receptor (Gq-mER) ligand, STX, rapidly increase membrane excitability in proopiomelanocortin (POMC) neurons by desensitizing the coupling of GABA_B receptors to G protein-coupled inwardly rectifying K⁺ channels (GIRKs), which upon activation elicit a hyperpolarizing outward current. However, it is unknown whether E2 and STX can modulate GABA_B signaling in neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons. We used single-cell RT-PCR and whole-cell patch clamping with selective pharmacological reagents to show that NPY/AgRP cells of mice express the GABA_B-R1 and -R2 receptors and are hyperpolarized by the GABA_B agonist baclofen in an E2-dependent manner. In males, E2 rapidly attenuated the coupling of GABA_B receptors to GIRKs, which was blocked by the general PI3K inhibitors wortmannin and LY294002 or the selective p110β subunit inhibitor TGX-221. The ERα selective agonist PPT mimicked the effects of E2. STX, in contrast, enhanced the GABA_B response in males, which was abrogated by the ER antagonist ICI 182, 780. In gonadectomized mice of both sexes, E2 enhanced or attenuated the GABA_B response in different NPY/AgRP cells. Co-perfusing wortmannin with E2 or simply applying STX always enhanced the GABA_B response. Thus, in NPY/AgRP neurons, activation of the Gq-mER by E2 or STX enhances the GABAergic postsynaptic response, whereas activation of ERα by E2 attenuates it. These findings demonstrate a clear functional dichotomy of rapid E2 membrane-initiated signaling via ERα versus Gq-mER in a CNS neuron vital for regulating energy homeostasis.