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Abemaciclib, a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) for oestrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer can rarely cause severe liver injury. We report a fatal case of abemaciclib-induced mixed hepatocellular-cholestatic injury progressing to liver failure. A Hispanic woman in her mid-60s with metastatic ER+/HER2- breast cancer developed progressive hepatocellular-cholestatic injury 1 month after starting abemaciclib with letrozole. She presented with jaundice, pruritus and dark urine. Labs showed markedly elevated bilirubin, liver enzymes and alkaline phosphatase. Liver biopsy revealed portal inflammation, bile duct injury, cholestasis and steatosis. Extensive work-up excluded other causes. Despite initial fall in transaminases with drug withdrawal and high-dose steroids, her condition progressed with rising bilirubin and worsening coagulopathy signalling progressive loss of hepatic synthetic function suggestive of impending liver failure and death. In clinical trial, any-grade transaminase elevation occurs in 14%-15% of patients receiving abemaciclib, with grade 3 hepatotoxicity in 2.9%-4.8%. In a retrospective cohort of patients receiving abemaciclib plus endocrine therapy, 29% (15/52) developed abemaciclib-induced liver injury (AILI), with age ≥65 years, fatty liver disease and concomitant aromatase inhibitor use identified as risk factors. Educating patients to recognise early symptoms of liver injury is essential for prompt detection and management of AILI. This case highlights the need for patient education, close liver monitoring, early cessation of abemaciclib and consideration of genetic risk factors in high-risk patients.