<p><i>Chrysanthemum morifolium Ramat</i>, a globally popular herb, often has its dry aboveground parts burned, discarded, or utilized as feed. To reintegrate and utilize the stem and leaves of <i>Chrysanthemum morifolium</i> Ramat (SLC), we prepared total flavonoid fractions from the stem and leaves of <i>Chrysanthemum morifolium</i> Ramat (SLTF) to ascertain the material basis and assess the potential hepatoprotective effects of SLTF. The chemical composition of SLTF was characterized using UPLC-Q-Exactive Orbitrap/MS, ultimately resulting in the identification of 36 compounds, including 23 flavonoids, 5 phenylpropanoid compounds and 2 organic acids. The pharmacodynamic assessments indicated that SLTF markedly mitigates hepatic inflammation and diminishes hepatic injury by suppressing serum levels of ALT and AST. Furthermore, SLTF enhances the activities of SOD and GSH-Px in the liver, while concurrently reducing MDA levels. Immunohistochemical analysis and Western blotting demonstrated that SLTF activates the Nrf2 signaling pathway, leading to the upregulation of Nrf2 expression, downregulation of Keap1 expression, and an increase in HO-1 levels. These findings suggest that SLTF exerts a protective effect on the liver through the activation of the Nrf2 pathway and the mitigation of oxidative stress. The results of this study provide valuable insights for the development and application of SLC as a promising source of antioxidants.</p> Graphical abstract <p></p>