Astrocytes express a variety of G protein–coupled receptors and might influence cognitive functions, such as learning and memory. However, the roles of astrocytic G_s-coupled receptors in cognitive function are not known. We found that humans with Alzheimer's disease (AD) had increased levels of the G_s-coupled adenosine receptor A_2A in astrocytes. Conditional genetic removal of these receptors enhanced long-term memory in young and aging mice and increased the levels of Arc (also known as Arg3.1), an immediate-early gene that is required for long-term memory. Chemogenetic activation of astrocytic G_s-coupled signaling reduced long-term memory in mice without affecting learning. Like humans with AD, aging mice expressing human amyloid precursor protein (hAPP) showed increased levels of astrocytic A_2A receptors. Conditional genetic removal of these receptors enhanced memory in aging hAPP mice. Together, these findings establish a regulatory role for astrocytic G_s-coupled receptors in memory and suggest that AD-linked increases in astrocytic A_2A receptor levels contribute to memory loss.