This study describes a mouse model for chronic and binge ethanol feeding, which mimics acute-on-chronic alcoholic liver injury in humans. The model involves chronic ethanol feeding (10 days of ad libitum feeding with the Lieber-DeCarli ethanol liquid diet) followed by a single binge ethanol feeding. This protocol synergistically induces liver injury, inflammation, and fatty liver, closely resembling the pathophysiology of alcoholic liver disease (ALD) in patients. The model can be extended to longer periods of chronic feeding (up to 8 weeks) with single or multiple binges. Chronic-binge ethanol feeding leads to high blood alcohol levels, making it useful for studying ALD and alcohol-related damage to other organs. The model is cost-effective and easy to perform, using C57BL/6 mice, which are the best strain for ad libitum ethanol feeding. Other strains may require acclimatization or have higher mortality rates. The model involves acclimatization to liquid diet feeding, chronic ethanol feeding, and a single binge ethanol gavage. The protocol includes detailed steps for preparing and administering the ethanol diet, gavage, and monitoring mice for liver injury markers such as serum ALT and AST levels. The model has been shown to induce significant liver injury, with peak serum ALT and AST levels 9 hours after gavage. It also reproduces the drinking behaviors and liver injury patterns seen in patients with ALD. The model has been validated against other animal models and human ALD, showing similar liver histology and biochemical changes. It is particularly useful for studying the effects of chronic and binge ethanol feeding on liver injury and other organ damage. The model can be adapted to study the effects of different dietary fats on ALD and has been used to examine the role of various factors in disease progression. The study highlights the importance of drinking patterns in ALD and provides a reliable model for further research into the mechanisms of alcohol-induced liver injury.This study describes a mouse model for chronic and binge ethanol feeding, which mimics acute-on-chronic alcoholic liver injury in humans. The model involves chronic ethanol feeding (10 days of ad libitum feeding with the Lieber-DeCarli ethanol liquid diet) followed by a single binge ethanol feeding. This protocol synergistically induces liver injury, inflammation, and fatty liver, closely resembling the pathophysiology of alcoholic liver disease (ALD) in patients. The model can be extended to longer periods of chronic feeding (up to 8 weeks) with single or multiple binges. Chronic-binge ethanol feeding leads to high blood alcohol levels, making it useful for studying ALD and alcohol-related damage to other organs. The model is cost-effective and easy to perform, using C57BL/6 mice, which are the best strain for ad libitum ethanol feeding. Other strains may require acclimatization or have higher mortality rates. The model involves acclimatization to liquid diet feeding, chronic ethanol feeding, and a single binge ethanol gavage. The protocol includes detailed steps for preparing and administering the ethanol diet, gavage, and monitoring mice for liver injury markers such as serum ALT and AST levels. The model has been shown to induce significant liver injury, with peak serum ALT and AST levels 9 hours after gavage. It also reproduces the drinking behaviors and liver injury patterns seen in patients with ALD. The model has been validated against other animal models and human ALD, showing similar liver histology and biochemical changes. It is particularly useful for studying the effects of chronic and binge ethanol feeding on liver injury and other organ damage. The model can be adapted to study the effects of different dietary fats on ALD and has been used to examine the role of various factors in disease progression. The study highlights the importance of drinking patterns in ALD and provides a reliable model for further research into the mechanisms of alcohol-induced liver injury.