Salvianolic acid B (Sal B) is one of the main water-soluble components of Salvia miltiorrhiza Bge. Numerous reports have demonstrated that it could exert significant renal-protective effects, but the underlying mechanism remains unclear. The present study demonstrated that Sal B could alleviate renal injury by regulating the heparanase/syndecan-1 (HPSE/SDC1) axis. In vivo, the serum creatinine, blood urea nitrogen, transforming growth factor-β1 (TGF-β1) and fibroblast growth factor-2 (FGF-2) levels, and the histopathological changes of mice kidneys were examined. Sal B could notably reduce the renal injury caused by left ureteral ligation. In vitro, Sal B downregulated the expression levels of HPSE/FGF-2/TGF-β1/α-smooth muscle actin and upregulated the expression levels of SDC1/E-cadherin in angiotensin II-stimulated HK-2 cells in a dose-dependent manner. In summary, to the best of the authors' knowledge, the present study provided evidence for the first time that Sal B could exert renal-protective effects via the inhibition of the HPSE/SDC1 axis, and these results suggest that the administration of Sal B may be a novel therapeutic strategy in treating renal interstitial fibrosis.