Yinchenzhufu decoction (YCZFD) is a traditional Chinese medicine formula with hepatoprotective effects. In this study, the protective effects of YCZFD against cholestatic liver fibrosis and its mechanisms of action were evaluated in a mouse model of 3,5-diethoxycarbonyl-1,4-dihydro-collidine (DDC)-induced cholestasis. YCZFD significantly decreased levels of serum biochemical, liver injury, and fibrosis indicators. Data-independent acquisition-based mass spectrometry (MS) was used to investigate proteomic changes in the livers of mice in three groups: control, model, and model treated by high-dose YCZFD. In total, 460 differentially expressed proteins (DEPs) were identified. Enrichment analyses of these DEPs uncovered that YCZFD influences multiple pathways, including PI3K-Akt, focal adhesion, ECM-receptor interaction, glutathione metabolism, and steroid biosynthesis pathways. PDGFRβ, a receptor associated with the PI3K/AKT and focal adhesion pathways, was significantly upregulated in the livers of cholestatic mice but downregulated by YCZFD. The effects of YCZFD on the expression levels of key proteins in the PDGFRβ/PI3K/AKT pathway were further confirmed in TGFβ-induced hepatic stellate cells. Finally, we uncovered six components (i.e., chlorogenic acid, scoparone, isoliquiritigenin, glycyrrhetinic acid, formononetin, atractylenolide I, and benzoylaconitine) of YCZFD that may regulate PDGFRβ expression. Overall, YCZFD exerts a substantial protective effect against DDC-induced cholestatic liver fibrosis mainly through regulating the PDGFRβ/PI3K/AKT signaling pathway.