Heart failure (HF) is a leading cause of death worldwide despite recent advances in pharmacological treatments. Gut microbiota dysbiosis and gut barrier dysfunction with consequent bacterial translocation and increased blood endotoxemia has gained much attention as one of the key pathogenetic mechanisms contributing to increased mortality of patients at risk or with cardiovascular disease. Indeed, increased blood levels of lipopolysaccharide (LPS), a glycolipid of outer membrane of gut gram-negative bacteria, have been detected in patients with diabetes, obesity and nonalcoholic fatty liver disease or in patients with established coronary disease such as myocardial infarction or atrial fibrillation, suggesting endotoxemia as aggravating factor via systemic inflammation and eventually vascular damage. Upon interaction with its receptor Toll-like receptor 4 (TLR4) LPS may, in fact, act at different cellular levels so eliciting formation of proinflammatory cytokines or exerting a procoagulant activity. Increasing body of evidence pointed to endotoxemia as factor potentially deteriorating the clinical course of patients with HF, that, in fact, is associated with gut dysbiosis-derived changes of gut barrier functionality and eventually bacteria or bacterial product translocation into systemic circulation. The aim of this review is to summarize current experimental and clinical evidence on the mechanisms linking gut dysbiosis-related endotoxemia with HF, its potential negative impact with HF progression, and the therapeutic strategies that can counteract endotoxemia.