<p>Diuretics are essential for managing fluid overload in heart failure (HF) and controlling blood pressure in hypertension. However, their use is often associated with complications such as electrolyte imbalances and neurohormonal dysregulation, which can limit their effectiveness and contribute to adverse outcomes. These challenges underscore the need for alternative or adjunctive strategies to better manage fluid retention and congestion. Osmolytes are small molecules that help counteract increases in extracellular osmotic and hydrostatic pressure and are naturally present at high concentrations in the renal medulla. Notably, elevated serum levels of osmolytes such as trimethylamine N-oxide (TMAO) and betaine have been observed in patients with HF, although their role in the pathophysiology of the disease remains unclear. Given the known diuretic properties of osmolytes such as urea—historically used in the management of HF—it is plausible that other osmolytes may similarly modulate diuresis and volume status. This review examines the biological actions of several key osmolytes, including urea, TMAO, betaine, and taurine. Emerging evidence supports the need for further preclinical and clinical studies to investigate the potential diuretic and cytoprotective effects of TMAO, betaine, and taurine in the prevention and treatment of HF and hypertension.</p>