Fibrosis occurs in a variety of organs and frequently brings great harm to patients, even contributes to their death. Despite great efforts made in the field of fibrosis over the past decades and considerable understanding of the pathogenesis of fibrotic reactions attained, there is still lack of effective anti-fibrotic treatments. A growing body of evidence indicates a significant anti-fibrotic potential of activated soluble guanylate cyclase (sGC), which emphasizes the importance of sGC in fibrogenesis of diverse organs including skin, kidney, liver and lung. While sGC has been well known for its role in the regulation of vascular tone and vascular remodeling, its possible implication in fibrosis remains to be illustrated. Emerging evidence in recent years provides new insights into anti-fibrotic effect of sGC stimulation by blocking non-canonical TGF-β signaling. In this review we will discuss the key role of sGC and its mechanism of action in fibrosis. Herein, sGC signaling pathway may represent a promising target for treating tissue fibrosis.