Background <p>Alcoholic liver disease (ALD) is a key cause of chronic liver disease worldwide, which progresses to liver cirrhosis and even hepatocellular carcinoma. After years of application and research, the traditional Chinese medicine (TCM) Exocarpium Citri Grandis (ECG) has shown the significant function of lowering lipid and outering the effect of drinking, but the specific mechanism of its action in ALD is not clear.</p> Purpose <p>The aim of this study is to investigate the anti-alcohol and lipid-lowering effects of ECG and its underlying pharmacological mechanisms in vitro and in vivo.</p> Methods <p>First, this study initiated with a preliminary identification of the active components in the aqueous extract of ECG. Then zebrafish, mice, AML-12 cells and RAW264.7 cells were used as the research object. Serum and hepatic iron concentration were assessed by biochemical assays and iron assay kits. Besides, cells were constructed with the receptor for advanced glycation endproducts (RAGE) overexpression virus for further research.</p> Results <p>ECG extract was low-toxicity and effectively alleviated alcohol-induced hepatic steatosis in mice and zebrafish. Besides, ECG extract intervention inhibited hepatic iron overload in ALD through mediating the iron-related pathways. Specifically, ECG reversed the down-regulation of ferroportin1 and up-regulation of hepcidin and ferritin in mice liver induced by alcohol, which subsequently suppressed iron dependent-lipid peroxidation and inflammation. In addition, flavonoids were the main components of ECG and could be combined with RAGE. The study indicated that ECG had a superior therapeutic effect against alcohol-induced liver injury in vivo and in vitro.</p> Conclusions <p>The protective effect of ECG might be closely related to the modulation of RAGE-mediated lipid accumulation and iron overload. The evidence provides the therapeutic promise of ECG in ALD.</p>