Background <p>Endotoxemia, a life-threatening syndrome, is a major cause of mortality worldwide and disrupts the internal environment of the body. This review thoroughly explores the complex relationship between endotoxemia, the hypothalamic-pituitary-adrenal axis (HPA), and the emerging neuropeptide neurotensin (NTS). It provides a detailed overview of how the HPA axis functions and its pathophysiology under endotoxemic conditions, as well as how it is influenced by NTS through NTS receptor 1 (NTSR1) signaling. Recent evidence suggests that endotoxemia disrupts the neuroendocrine system and the HPA axis, which responds to various stress-inducing stimuli (such as Lipopolysaccharide/ LPS), leading to the development and progression of metabolic, cardiovascular, neurological, and depressive disorders, including obesity, pulmonary hypertension, stroke, schizophrenia, Parkinson’s, Alzheimer’s, and adrenal-related conditions. Studies on NTS as a neuro-immune modulator and a key regulator of the HPA axis are currently underway.</p> Methodology <p>A literature search was conducted by taking articles from PubMed, Scopus, Google Scholar, and Web of Science to gather relevant studies published until July 2025. We employed a combination of keywords and phrases related to endotoxemia, HPA axis, and neurotensinergic system, retrieving more than 10,000 articles, and among them, relevant articles were incorporated in the final study.</p> Conclusion <p>Research has shown that this intriguing peptide can reduce or reverse the severity of endotoxemia and HPA dysfunction primarily through anti-inflammatory, antioxidant, and barrier-protective mechanisms. In an effort to enhance our understanding of the interactions between NTS and endotoxemia-induced HPA dysfunction, this review aims to summarize the multifaceted role of NTS and the potential of its analogs (agonists/antagonists) as therapeutics for various stress-related disorders.</p> Graphical Abstract <p></p>