Abstract: Background: Spatholobus suberectus Dunn (SSP), a traditional herb used to improve blood circulation and ease pain, exhibits multiple biological functions. However, its therapeutic role in hepatic fibrosis, along with the underlying molecular mechanisms and active components, remain largely unclear. Objective: To investigate the anti-fibrotic efficacy of SSP in vivo and in vitro models and to elucidate its potential mechanism. Methods: C57BL/6J mice were fed a choline-deficient high-fat diet (CDHFD) or administered carbon tetrachloride (CCl₄) to build steatohepatitis or fibrosis, followed by SSP intervention. In vitro, FFA-treated hepatocytes and TGF-β1-activated hepatic stellate cells (HSCs) were used. Histology, western blotting, RT-qPCR, and transcriptomics were performed to assess therapeutic effects and mechanisms. Candidate molecules were further evaluated by knockdown and overexpression, and the active components were evaluated by CETSA, supported by docking and molecular dynamics simulation. Results: SSP alleviated hepatic lipid deposition, inflammation, and fibrosis in CDHFD-induced in vivo and FFA-treated in vitro models. Transcriptomics together with MFAP4 knockdown and overexpression indicated that SSP suppressed fibrosis through the MFAP4/TGF-β1/LOXL1 axis, thereby inhibiting HSCs activation and extracellular matrix (ECM) generation, as further supported by CCl₄ -induced in vitro and TGF-β1-induced HSCs in vivo models. Molecular docking, dynamics simulations, and CETSA suggested that luteolin and genistein may be key components in modulating MFAP4. Conclusion: SSP works to alleviate liver fibrosis by reducing hepatocyte metabolic stress and directly suppressing HSCs activation via the MFAP4-mediated TGF-β1/LOXL1 feedback loop. Genistein and luteolin may represent key bioactive constituents, supporting SSP as a multi-target strategy for liver fibrosis.