Delirium is a frequent form of acute brain dysfunction in patients who are critically ill and is associated with poor clinical outcomes, including a critical illness brain injury that may last for months to years. Despite widespread recognition of significant adverse outcomes, pharmacologic approaches to prevent or treat delirium during critical illness remain unproven. We hypothesize that commonly prescribed statin medications may prevent and treat delirium by targeting molecular pathways of inflammation (peripheral and central) and microglial activation that are central to the pathogenesis of delirium. Systemic inflammation, a principal mechanism of injury, for example, in sepsis, acute respiratory distress syndrome, and other critical illnesses, can cause neuronal apoptosis, blood-brain barrier injury, brain ischemia, and microglial activation. We hypothesize that the known pleiotropic effects of statins, which attenuate such neuroinflammation, may redirect microglial activation and promote an antiinflammatory phenotype, thereby offering the potential to reduce the public health burden of delirium and its associated long-term cognitive injury.