Post-hepatectomy liver failure (PHLF) is a potentially fatal complication following liver surgery, characterized by impaired hepatic synthetic, excretory, and detoxifying function. Despite advances in surgical techniques and perioperative management, clinically-significant PHLF remains difficult to treat and associated with high mortality rates. This chapter reviews current therapeutic strategies for established PHLF, emphasizing evidence-based supportive measures and emerging interventions. Key components of management include hemodynamic optimization, nutritional support, infection control, and management of coagulopathy, renal, and pulmonary dysfunction. Liver-directed therapies, though largely supportive, may include pharmacologic agents such as N-acetylcysteine and ammonia-lowering treatments, while extracorporeal liver support systems such as molecular adsorbent recirculating system (MARS) offer temporary detoxification in selected patients. Timely intervention in biliary and vascular complications, if present, may counteract hepatic deterioration. Liver transplantation remains the only definitive treatment for irreversible PHLF, though eligibility is often constrained by oncologic and technical factors; living donor and auxiliary transplantation strategies may expand options in select cases. Emerging therapies—including stem cell treatments, bioartificial liver devices, and normothermic ex situ liver perfusion—represent promising future avenues for regenerative liver support. Overall, optimal PHLF management hinges on early recognition, multidisciplinary coordination, and individualized care, with evolving technologies offering potential to enhance outcomes in this complex clinical scenario.