The present study was undertaken to evaluate the hepatoprotective effect mechanisms of Nelumbo nucifera leaves extract (NLE) in experimental alcoholic steatohepatitis animal models. We found that the NLE contained polyphenols (phenolic acids and flavonoids), and more than 70% of the main functional components in NLE could potentially provide benefits for alcoholic liver disease. The parameters of histopathology, immunohistochemistry, antioxidant defense, proinflammatory mediator and lipid synthesis-related proteins demonstrated the inhibitory effect of NLE on alcoholic steatohepatitis. Plasma and hepatic content analysis showed that NLE inhibited lipid accumulation by altering the levels of triglycerides (TG) and cholesterol (TC). Treatment with NLE increased the expression of the p-AMPK/AMPK ratio and PPAR-α. Furthermore, fatty acid oxidation and transport via carnitine palmitoyltransferase-1 (CPT1) and microsomal triglyceride transfer protein (MTP) were through the activation of the AMPK and PPAR-α signal. These results revealed that the polyphenol-rich component of NLE prevents alcoholic steatohepatitis by multiple pathways, including reduced lipid synthesis, enhanced fatty acid oxidation and transport responses, inhibited oxidative stress and facilitated anti-inflammation. Suggesting that NLE might be regarded as a beneficial food that has the potential to be developed as a natural agent for preventing alcoholic steatohepatitis.