Alzheimer’s disease (AD) is a debilitating dementia that affects about seven million Americans. Oligodendrocytes and myelin degeneration have been noted as features of AD, with demyelination beginning in preclinical disease. However, the mechanisms underlying oligodendrocyte and myelin decay remain poorly understood. Here, we show how transcriptional stress coupled-DNA damage accumulates in preclinical disease, and outline a novel pathway downstream of this DNA damage resulting in activation of the Type I interferon response. In vitro, we find that upon DNA damage, oligodendrocytes activate Stimulator of Interferon Genes (STING), a mediator of the DNA damage-Type I interferon signaling axis, and this drives myelin deficits in vitro. Oligodendrocyte lineage-specific deletion of STING in the 5XFAD murine AD model reduces demyelination, microgliosis, neurodegeneration, and plaque formation. Finally, loss of STING in oligodendroglial cells rescues deficits in spatial memory and learning in the 5XFAD model, as shown by Barnes Maze latencies. Our findings uncover a previously overlooked and key role for oligodendrocytes as active drivers of neurodegeneration in Alzheimer’s Disease.