The cellular mechanisms underlying cognitive impairments in heart failure (HF) remain unknown. Although HF-induced neuroinflammation and hypoxia in the hippocampus have been reported in humans and rodents, whether and how these processes are causally connected remains unexplored. Here we report that microglial Angiotensin II (AngII) signaling in the hippocampus is a crucial component in HF-induced neuroinflammation. We found microglial-specific upregulation of the AngII receptor AT1a that coincided with a hypoxic state, but preceded cytokine production. In addition to hippocampal apoptotic clusters, HF rats displayed progressive angiogenesis, migration of AT1a-positive microglia to blood vessels, and disruption of BBB integrity. Treatment of HF rats with the AT1 receptor antagonist losartan reversed neuroinflammation (but not hypoxia), apoptosis and cognitive impairments in HF rats. Taken together, we present here a novel mechanism by which microglial AngII signaling triggers a microglia-dependent neuroinflammatory cascade that contributes to neuronal apoptosis, hippocampal structure deterioration and cognitive decline.