AbstractAcid‐Sensing Ion Channel 2 (Asic2) is expressed in many brain regions, including the hypothalamus, the homeostatic center for hunger‐satiety‐energy expenditure. We used the HypoMap reference atlas of the mouse hypothalamus to localize Asic2 message in the specific hypothalamic regions and found that Asic2 is the predominant degenerin subunit expressed in mouse hypothalamic neurons in the ventromedial, lateral, and arcuate regions and is expressed in pro‐opiomelanocortin (Pomc), agouti‐related peptide (Agrp), as well as leptin (Lepr) and insulin receptors (Insr) positive neurons. Thus, we investigated if Asic2 plays an important role in body weight control and energy expenditure before and after high‐fat diet (HFD). Asic2−/− male mice had lower lean body mass. On normal chow, Asic2−/− mice consumed more food, displayed elevated total energy expenditure, and a higher respiratory exchange ratio compared to WT mice. On the HFD, Asic2−/− female mice had greater motor activity and resting and total energy expenditure. We found no effect of genotype on plasma glucose, insulin, or ghrelin levels; however, leptin was elevated in male Asic2−/− mice following the HFD. Our findings suggest that Asic2 plays an important role in metabolic homeostasis, possibly through regulation of central pathways involved in energy balance.