Hyperbaric oxygen therapy (HBOT) is being increasingly recognized as a potential therapeutic modality with favorable mechanisms in various diseases. HBOT has demonstrated anti-inflammatory and antiapoptotic effects as well as increased the oxygenation capacity of oxygen-deprived tissues, thus contributing to tissue homeostasis. Focusing on these mechanisms, HBOT could be applied for sepsis-associated encephalopathy (SAE), which is a serious sepsis-related complication. Two vital mechanisms in the pathogenesis of SAE are: (1) neuroinflammation mainly induced by microglia and (2) cerebral ischemia/hypoperfusion caused by cerebral microcirculatory abnormalities. Herein, we highlight the mechanisms of the neuroprotective effects of HBOT and its potential application as a therapeutic modality for SAE. We also discuss the caveats and limitations of applying HBOT in sepsis.