<p>Small Interfering RNA (siRNA) is a class of double-stranded, noncoding RNA that silences pathogenic mRNA through the process of RNA interference (RNAi). Its medical application is extensive, particularly in targeting genes associated with cardiorenal diseases, including atherosclerosis, chronic kidney disease, hypertension and cardiac failure. The pathophysiology of cardiorenal syndrome is intricate, involving a network of neurohormonal, metabolic, hemodynamic, and inflammatory interactions. Thereby, this review emphasizes the mechanistic pathways and provides evidence from preclinical and clinical studies underscoring the therapeutic potential of siRNA in the cardiorenal axis. siRNA has been shown to alleviate hemodynamic stress, reduce inflammatory cytokines and disease biomarkers. Additionally, advancements in delivery systems are explored, with a focus on overcoming challenges such as poor stability, off-target effects and limited absorption to enhance clinical applicability. This review highlights the development of siRNA-based therapeutic strategies within the cardiorenal axis, emphasizing a molecular understanding of the underlying mechanisms.</p> Graphical Abstract <p>An illustration of potential role of siRNA and its implication in cardiorenal axis. The current review explores the siRNA based molecular mechanisms of oxidative stress, inflammation and endothelial dysfunction, fibrosis and apoptotic molecules involved in cardiac and renal failure. In future provides an understanding of the siRNA-based treatment approaches in preventing the cardiorenal axis with pre-clinical and clinical evidences.</p> <p></p>