Sepsis-associated encephalopathy (SAE) describes acute cognitive dysfunction secondary to systemic or peripheral infection occurring outside of the central nervous system (CNS). Symptoms can range from mild confusion to coma and may precede the clinical signs of sepsis. Recognition that SAE is a potential differential diagnosis in patients presenting with delirium is important, as SAE is a diagnosis of exclusion. Physicians should also be aware that severe SAE is associated with a high mortality. Although mortality is often secondary to multiorgan failure rather than neurological sequelae, long-term cognitive and psychological morbidities have been reported in sepsis survivors. Early treatment (which can include prompt identification and source control of the infection) and good supportive care might improve cognitive outcomes. Future work should aim to improve understanding of both acute and chronic SAE with a focus on therapeutic interventions and improving patient outcomes.