Acetaminophen (APAP) is a widely used drug in our environment with few adverse effects. Because of this, several patients affected by APAP hepatotoxicity unknown that the APAP dose-intake was excessive. This damage is mainly produced via one of APAP metabolites: N-acetyl-para-benzo-quinone imine (NAPQI), which is very toxic. The drug’s ingested doses as well as the length of time from APAP ingestion to N-acetylcysteine (NAC) therapy are the most essential determining factors in both the development and severity of APAP hepatotoxicity. However, there are other factors related, including alcohol intake, herbs and medications, age and genetic factors, nutritional status, and chronic liver disease. The ingestion of a toxic dose of APAP causes different clinical manifestations that depend fundamentally on the time elapsed since the intake. The diagnosis process depends on the intake (acute single overdose of after repeated overdoses). The Rumack-Matthew nomogram is acceptable after an acute single overdose, being the “possible hepatic toxicity” point 200 μg/mL at 4 hours and 25 μg/mL at 16 hours). This normogram is no applicable in after repeated overdoses. NAC is the antidote for APAP intoxication, and could be administered orally or intravenous. Finally, a multidisciplinary approach with the support of Psychiatry, Intensive Care Unit as well as Gastroenterology and Digestive Department will be necessary, especially in the case of attempted autolysis and severe liver failure.