Glucagon-like peptide 1 (GLP-1)-based therapeutics are very effective for treatments for obesity and type 2 diabetes but unfortunately often produce nausea and emesis leading to treatment discontinuation. The area postrema (AP) and the nucleus of the solitary tract (NTS), two adjacent hindbrain nuclei, play a key role in the mediation of nausea and emesis induced by GLP-1 therapeutics. Current pre-clinical research has shown that glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism enhances the beneficial effects of GLP-1-based therapeutics while simultaneously reducing the occurrence and intensity of nausea and emesis. However, little is known about the neuronal pathways and behavioral mechanisms mediating the anti-emetic effects of GIPR agonism. Here, we focused on a distinct population of GIPR neurons within the AP/NTS which has been found to co-express the inhibitory neurotransmitter GABA. Using chemogenetic approaches, we first examined the effects of selective activation or inhibition of GABA-ergic neurons in the AP/NTS alone or in combination with the long-acting FDA-approved GLP-1R agonist semaglutide on food intake, malaise and body weight in rats. Next, by taking advantages of various GABA analogs, the effect of pharmacological activation of GABA receptors alone or in combination with GLP-1R activation was examined in rats. Our data demonstrated that chemogenetic activation of AP/NTS GABA-ergic neurons alone produced profound hypophagia, body weight loss, and reduced gastric emptying without causing malaise. Additionally, chemogenetic activation of AP/NTS GABA-ergic neurons enhanced semaglutide induced anorexia and weight loss, and importantly, attenuated semaglutide induced malaise. In contrast, pharmacological approaches targeting GABA receptors largely failed to affect feeding and to ameliorate GLP-1R mediated nausea. Furthermore, we discovered that GIPR agonism leads to direct activation of 25% of GABA-ergic neurons within the AP/NTS through immunohistochemistry staining. Together, these results point to a key role of a subpopulation of GABA-ergic neurons that co-express GIPR, as understudied modulators of feeding and illness-like behaviors and provide a neuroanatomical and mechanistic explanation for the anti-emetic effects of GIPR agonisms.