Adipose-derived stem cells (ADSCs) demonstrated therapeutic potential in various fibrotic diseases, with their paracrine proteins playing a crucial role. Nonetheless, the principal paracrine factors of ADSCs responsible for antifibrosis have not yet been well identified. To address this issue, we initially confirmed that ADSCs could attenuate fibrosis and suppress TGF-β1 in bleomycin-induced skin fibrosis mouse models. RNA-sequencing of the cocultured fibroblasts demonstrated that ADSCs effectively inhibited the TGF-β/Smad2 signaling pathway in fibroblasts through the paracrine approach. Proteomic analysis of the cell supernatant (CS) demonstrated a significant upregulation of 97 proteins in the secretome of ADSCs, among which decorin (DCN) exhibited a particularly elevated level of overexpression. Protein–protein interaction (PPI) network analysis indicated a strong correlation between DCN and TGF-β1, with DCN effectively trapping TGF-β1 through core protein binding. Cell experiments demonstrated that DCN could effectively inhibit TGF-β1-induced fibroblast proliferation. Therefore, it was concluded that DCN was a crucial protein in ADSC secretome that exerted antifibrotic effects by inhibiting TGF-β1. This study conducted an in-depth insight into the paracrine function of ADSCs through transcriptome and proteome analysis, identifying DCN as an essential paracrine factor mediating the antifibrotic effect of ADSCs, which could provide valuable theoretical support for the use of ADSC secretions as well as DCN in the treatment of fibrotic diseases.