Systemic sclerosis (SSc) refers to a group of autoimmune rheumatic diseases. Bushen Yijing decoction (BSYJ) is used for treating SSc. However, its underlying mechanism remains unknown. The present study aims to investigate potential roles of Friend leukemia integration factor 1 (FLI1) and microRNA in the beneficial effects of BSYJ on SSc. Primary skin fibroblasts were isolated from healthy individuals and SSc patients through tissue-explant technique and validated by immunocytochemistry. mRNA and microRNA levels were determined by quantitative RT-PCR. Protein expression was measured by western blotting. MiR-26a mimics or inhibitor were transfected to induce miR-26a overexpression or knockdown in vitro and in vivo, respectively. Histological changes of skin tissues from SSc mouse were evaluated by H&E and Masson trichrome staining. Results showed that FLI1 expression significantly decreased in primary skin fibroblasts of SSc patients. MiR-26a was predicted to target FLI1 untranslated region. Transfection of miR-26 mimics in SSc skin fibroblasts (SFB) leads to decrease in FLI1 expression and increase in collagen I gene expression and fibronectin accumulation. On the other hand, miR-26a knockdown increased FLI1 expression and decreased collagen I and fibronectin expression in SFB. In addition, BSYJ-containing rat serum suppressed miR-26a expression, while it elevated FLI1 expression and inhibited fibronectin and collagen I accumulation in SFB. In the mouse SSc model, BSYJ-containing serum inhibited dermal fibrosis by suppressing miR-26a expression and restoring FLI1 protein levels. Overall, our study demonstrates that BSYJ decoction exerts anti-dermal fibrosis in SSc patients via suppressing miR-26a level and thus to increase FLI1 expression in fibroblasts.