Alzheimer's disease (AD) is the leading cause of dementia and there are no effective treatments for this disease currently. Circadian rhythm disruption (CRD) is a hallmark of modern society that appears to be on the rise. It is well reported that AD is associated with disrupted circadian functioning and CRD can impair cognitive function. However, the cellular mechanisms underlying CRD-associated cognitive decline remain elusive. In this study, we investigated whether microglia are involved in CRD-induced cognitive decline. We established experimental 'jet lag' (phase delay of the light/dark cycles)-induced CRD mouse model and observed significant impairment of spatial learning and memory function in these mice. In the brain, CRD resulted in neuroinflammation, which was characterized by microglia activation and increased pro-inflammatory cytokine production, impairments in neurogenesis and reduction of synaptic proteins in the hippocampus. Interestingly, elimination of microglia with the colony stimulating factor-1 receptor inhibitor PLX3397 prevented CRD-induced neuroinflammation, cognitive decline, impairment of neurogenesis and loss of synaptic proteins. These findings collectively suggest that microglia activation plays a key role in CRD-induced cognitive deficit most likely through neuroinflammation-mediated impairments in adult neurogenesis and synapses.Copyright © 2023. Published by Elsevier B.V.