Glucagon-like peptide 1 (GLP-1)-based therapeutics and chemotherapeutic agents are very effective for treatments for obesity, type 2 diabetes, and cancer respectively, 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 and chemotherapy. 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 examined the effects of selective activation of these (GABA-ergic) neurons in the AP/NTS in combination with the long-acting FDA-approved GLP-1R agonist semaglutide or chemotherapeutic agent cisplatin on food intake, malaise and body weight in rats. Our data demonstrated that activation of AP/NTS GABA-ergic neurons alone produced profound hypophagia and body weight loss without causing malaise. Additionally, chemogenetic activation of AP/NTS GABA-ergic neurons enhanced semaglutide and cisplatin induced anorexia and weight loss, and importantly, attenuated malaise induced by the treatments. The increased hindbrain GABA signaling also decreased the gastric emptying rate which could be a contributing factor to the observed hypophagic effect. Together, these results point to a key role of GABA-ergic neurons as understudied modulators of feeding and illness-like behaviors and provide a neuroanatomical and mechanistic explanation for the anti-emetic effects of GIPR agonisms.