SignificanceAlthough significant progress in recent years has been made in defining key innate immune receptors involved in Alzheimer’s disease (AD), our knowledge of the specific intracellular signaling molecules that coordinate immune responses in AD remains poorly defined. In these studies, we have identified a previously undescribed role for the innate immune signaling molecule CARD9 in the 5xFAD mouse model of AD. We specifically demonstrate that CARD9 deletion in 5xFAD mice leads to impaired control of Aβ, worsened cognitive decline, and aberrant microglial activation. We further show that pharmacological activation of CARD9 boosts Aβ clearance in the hippocampus. Collectively, these findings uncover CARD9 as a molecular signaling molecule used by the innate immune system in Aβ-mediated neurological disease.