High-Pressure Nervous Syndrome (HPNS) refers to a series of neurological disturbances that occur during exposure to high hydrostatic pressure, characterized by cognitive and motor impairment manifestations. This review systematically summarizes the research progress on the pathophysiological mechanisms of HPNS. The main mechanism is the imbalance between inhibition of synaptic transmission and the increased excitability of neural networks, specifically involving voltage-gated sodium, potassium, calcium channels, and N-methyl-D-aspartate (NMDA) receptors. Most HPNS symptoms subside upon returning to normal pressure, making the study of its mechanisms challenging. HPNS remains a significant limiting factor for deep-sea diving, and to date, no effective drugs have been developed for human HPNS prevention. This review focuses on the pathophysiological mechanisms of HPNS, which is crucial for further understanding its mechanisms and extending the limits of human deep-sea diving.