The hypoxia-inducible factors prolyl hydroxylase domain inhibitor (HIF-PHI) appears to open a new door for the treatment of renal anemia, which is one of the most common complications of chronic kidney disease (CKD). However, the effects of HIF-PHI on renal function remain unknown. Here, the potential effects of Roxadustat (FG-4592), an orally administered HIF-PHI, on renal fibrosis were explored. In this study, the CKD rat model was induced by subtotal 5/6 nephrectomy (5/6 Nx). The CKD rats were treated with FG-4592 or vehicle by oral gavage three times per week for 12 weeks. Furthermore, the CKD rats were infused with recombinant FGF23 using Alzet osmotic pumps for 28 days. Accordingly, we found that CKD-induced anemia was significantly ameliorated. Meanwhile, markedly alleviated histopathological changes and renal tubulointerstitial fibrosis (TIF) were observed in rats with FG-4592 administration. More interestingly, we found that circulating level of intact FGF23 (iFGF23) was markedly reduced in CKD rats with FG-4592 treatment. The same result was also confirmed in CKD patients with Roxadustat treatment. Mechanistically, we illustrated that inhibition of the FGF23-WNT5A pathway is the exact mechanism by which FG-4592 ameliorated TIF. Further, we also demonstrated that transcriptional activation of Furin enzyme is the exact molecular mechanism for FG-4592-mediated iFGF23 cleavage. In conclusion, FG-4592 attenuated TIF by promoting iFGF23 cleavage, which is cleaved by Furin protease. These findings not only provide novel insights into the effects of HIF-PHI on renal function, but also provide important theoretical basis for clinical practice.