Agouti-related peptide (AgRP)-expressing neurons of the hypothalamus are the main neuronal population that mediate the effects of ghrelin, an appetite-stimulating peptide secreted from the stomach. Deletion of ghrelin receptor (GHSR, for growth hormone secretagogue receptor) from AgRP neurons blocks, whereas the expression of GHSR exclusively in AgRP neurons restores, ghrelin’s orexigenic effects. However, a thorough analysis of the hypothalamic neuronal subpopulations of ghrelin sensing neurons is still missing. Here, we first performed a detailed neuroanatomical analysis of the distribution of AgRP neurons that bind ghrelin in brain slices of mice that express Td-Tomato fluorescent protein exclusively in AgRP neurons that were centrally or peripherally administered with a fluorescent ghrelin analog. Using c-Fos expression, we also analyzed the distribution of AgRP neurons activated by ghrelin administration. Since previous results of our laboratory indicated that ghrelin administration triggers a sustained activation of AgRP neurons, we investigated the role of this effect on the orexigenic effect of ghrelin. We used mice expressing an inhibitory DREADD to analyze the involvement of AgRP neurons activation on the prolonged orexigenic effects of ghrelin. Our results suggest that ghrelin sensitive and ghrelin responsive AgRP neurons display a similar distribution in the mouse brain and that the blockade of AgRP activity abolishes the prolonged orexigenic effect of ghrelin.