Systemic sclerosis (SSc) is a connective tissue disease characterized mainly by fibrosis of skin and internal organs. Our previous study has shown that salvianolic acid B (SAB), a bioactive component extracted from Salvia miltiorrhiza (SM), was one of the essential ingredients in the traditional Chinese medicine Yiqihuoxue formula, which has been used to treat SSc-related dermal and pulmonary fibrosis. The aim of the present study was to evaluate the effect of SAB on skin fibrosis and explore its underlying anti-fibrotic mechanism. We found that SAB was capable of alleviating skin fibrosis in a bleomycin-induced SSc mouse model, alleviating skin thickness and reducing collagen deposition. in vitro studies indicated that SAB reduced SSc skin fibroblast proliferation and downregulated extracellular matrix gene transcription and collagen protein expression. TGF-β/SMAD and MAPK/ERK pathway activation were also shown to be suppressed in SAB treated fibroblasts. Moreover, RNA-seq revealed that the anti-fibrotic effect of SAB might be related to antioxidant activity, the cell cycle, and the p53 signaling pathway. Taken together, our results suggest that SAB has the ability to alleviate SSc-related skin fibrosis both in vivo and in vitro.