Fibrosis plays a crucial role in the development of cardiac remodeling following acute myocardial infarction (AMI). A novel Danshensu/tetramethylpyrazine derivative (ADTM) has exhibited promising outcomes in the treatment of cardiovascular diseases. However, its impact on cardiac fibrosis remains incompletely understood. In this study, cardiac fibrosis was induced in rats by ligating the left anterior descending coronary artery for 28 days. ADTM demonstrated significant cardioprotective effects. This was evidenced by the alleviation of cardiac dysfunction, a reduction in fibrosis, and the mitigation of endothelial-mesenchymal transition (EndMT) in heart failure rats. In vitro experiments showed that ADTM inhibited cell migration, proliferation, collagen secretion, and EndMT in both TGF-β1-treated neonatal rat cardiac fibroblasts (CFs) and human coronary artery endothelial cells (HCAECs). Through network pharmacology and molecular docking, matrix metalloproteinase 3 (MMP3) was identified as a potential drug target of ADTM. ADTM suppressed MMP3 upregulation in post-MI hearts and TGF-β1-treated cells, confirming MMP3 as a downstream target of Wnt/β-catenin signaling. Furthermore, the inhibition of MMP3 or β-catenin alleviated the activation of CFs and EndMT in HCAECs in vitro. These findings indicate that ADTM exerts antifibrotic effects by inhibiting MMP3, a potential target of the Wnt/β-catenin pathway. Thus, ADTM represents a novel therapeutic agent for cardiac fibrosis.