Objective <p>The leaves of <i>Malus hupehensis</i> (MH) are a medicinal and edible TCM with good liver protection, although its underlying mechanism remains unclear. In this study, a network pharmacology-integrated multiomics method was used to explore the hepatoprotective mechanism of MH.</p> Methods <p>The in vivo and in vitro components of MH were identified using ultra–performance liquid chromatography coupled with Q Exactive Orbitrap mass spectrometry (UPLC–Q Exactive Orbitrap–MS), and the targets and related pathways through which MH inhibits acute liver injury (ALI) were predicted by network pharmacology. The liver protective potential of MH was evaluated in a carbon tetrachloride-induced ALI model in C57BL/6J mice. The mechanism of MH was explored by integrating network pharmacology and multiomics and verified by immunohistochemistry, Western blot and RT‒qPCR analyses.</p> Results <p>Our analysis revealed 121 in vitro and 20 in vivo components of MH. The network pharmacology analysis showed that the prototype components of MH, phlorizin and phloretin, were involved in inflammation and metabolism-related pathways. In vivo experiments revealed that MH significantly inhibited carbon tetrachloride-induced ALI in mice through antioxidant and anti-inflammatory effects. Combined network pharmacology and multiomics analyses revealed that MH protected the liver by inhibiting the activation of the MAPK signaling pathway and regulating metabolic reprogramming, specifically with respect to lipid and amino acid metabolism.</p> Conclusions <p>Our study suggests that MH exerts a protective effect on carbon tetrachloride-induced ALI in mice, potentially by inhibiting MAPK signaling and regulating lipid and amino acid metabolic reprogramming. These findings provide a preliminary basis for exploring MH as a potential candidate for the prevention and treatment of ALI.</p> Graphical Abstract <p></p>