Renal fibrosis is the final common pathway of all varieties of progressive chronic kidney disease. However, there are no effective therapies to prevent or slow the progression of renal fibrosis. Niclosamide is a US Food and Drug Administration–approved oral antihelminthic drug used for treating most tapeworm infections. Here, we demonstrated that phosphate niclosamide, the water-soluble form of niclosamide, significantly reduced proteinuria, glomerulosclrotic lesions, and interstitial fibrosis in a murine model of adriamycin nephropathy. In addition, phosphate niclosamide significantly ameliorated established renal interstitial fibrosis a murine model of unilateral ureteral obstruction. Mechanistically, phosphate niclosamide directly inhibited TGF-β-induced expression of homeodomain-interacting protein kinase 2 (HIPK2) by interfering with the binding of Smad3 to the promoter of the HIPK2 gene, and subsequently mitigated the activation of its downstream signaling pathways including Smad, Notch, NF-κB and Wnt/β-catenin pathway both in vitro and in vivo. Thus, phosphate niclosamide mitigates renal fibrosis at least partially by inhibiting HIPK2 expression. Hence, phosphate niclosamide might be a potential therapeutic agent for renal fibrosis.