The recent advancements in the medical management of patients with chronic heart failure with reduced ejection fraction (HFrEF) is the soluble guanylate cyclase (sGC) stimulator, vericiguat. Clinical trials have demonstrated that vericiguat effectively lowers plasma levels of NT-proBNP and reduces the risk of cardiovascular death or hospitalization in HFrEF patients, making it a class IIb recommendation for patients with worsening heart failure despite receiving guideline-directed medical therapy. However, the precise pathophysiological mechanisms underlying these clinical benefits remain unexplored. This review aims to present the signalling pathways associated with maladaptive remodeling and heart failure progression that can be modulated by sGC stimulators, focusing on the antihypertrophic, antifibrotic, and anti-inflammatory effects of NO-sGC-cGMP signalling observed in preclinical studies. A better understanding of the mechanisms of action of sGC stimulators could optimize heart failure treatment strategies and enable tailoring of therapies to individual patient profiles.