Postoperative liver failure (POLF) is a serious complication following major liver surgery, marked by the liver’s inability to maintain vital metabolic and detoxification functions. Its multifactorial pathogenesis involves small-for-size syndrome, ischemia–reperfusion injury, portal hypertension, and impaired regeneration, often worsened by mitochondrial dysfunction and immune dysregulation. Accurate preoperative evaluation and intraoperative management are critical to reducing risk. Despite improvements in surgical strategies, POLF treatment remains largely supportive, underscoring the need for preventive approaches and innovative therapies.