Soluble biglycan, a small leucine-rich proteoglycan, plays a significant role in several pathologies as it has emerged as an extracellular matrix-derived danger-associated molecular pattern. Biglycan is released from the extracellular matrix in response to tissue injury and, as a canonical danger signal, interacts with innate immune receptors, Toll-like receptors 2 and 4, thereby triggering a sustained inflammatory response. Recent evidence indicates that biglycan acts as a molecular switch between inflammation and autophagy by a specific interaction with the Toll-like co-receptor CD14 and CD44, respectively. Biglycan-evoked autophagy further contributes to the anti-inflammatory M2 macrophage polarization, inflammation resolution and tissue repair. These multivalent roles of soluble biglycan have been well characterized in inflammatory kidney diseases. In chronic liver diseases, increased levels of soluble biglycan have been described for years, leading to utilization of biglycan serum levels as a non-invasive biomarker for fibrosis. Hepatorenal dysfunction represents a classic example of inter-organ crosstalk, in which functional and molecular alterations of the cirrhotic liver can promote the development of renal failure. In patients with liver cirrhosis, development of hepatorenal syndrome is associated with high mortality. In this review, we will discuss the crucial role of soluble biglycan in inflammation and autophagy and its possible implications for hepatorenal dysfunction. We propose a novel concept of hepatorenal crosstalk, that is, biglycan produced by the cirrhotic liver could constitute a circulating “messenger” for the kidneys triggering inflammation and/or autophagy ultimately affecting disease outcome.