Anti-cardiac fibrosis (CF) is one of the key therapeutic strategies for the treatment of various heart diseases. Therefore, development of drugs targeting CF is promising. However, there are very few studies that systemically explore effective drugs for CF. It has been known that many natural compounds display antifibrosis effects. In this work, we aim to build an integrated model for systematic pursuit of anti-CF agents from natural compounds. We first constructed a heart-specific CF marker-gene-centered functional gene module (HCFM) that represents a set of genes specifically involved in CF based on the CF marker genes and known gene coexpression knowledge. Then, we extracted transcriptional data induced by natural compounds from the Gene Expression Omnibus database. The anti-CF effects of compounds were evaluated by the correlation of HCFM in the compound-induced gene expression profiles by gene set enrichment analysis. Finally, the anti-CF effect of a top-predicted natural monomer, schisantherin A, was experimentally validated in the myocardial infarction animal model. This strategy integrating different types of technologies is expected to help create new opportunities for development of drugs targeting CF.