BACKGROUND: The adverse effect of excessive salt intake has been recognized in decades. Researchers have mainly focused on the association between salt intake and hypertension. However, studies in recent years have proposed the existence of extra-renal sodium storage and provided insight into the immunomodulatory function of sodium. OBJECTIVES: In this review, we discuss the modulatory effects of high salt on various innate and adaptive immune cells and immune-regulated diseases. METHODS: We identified papers through electronic searches of PubMed database from inception to March 2022. RESULTS: An increasing body of evidence has demonstrated that high salt can modulate the differentiation, activation and function of multiple immune cells. Furthermore, a high-salt diet can increase tissue sodium concentrations and influence the immune responses in microenvironments, thereby affecting the development of immune-regulated diseases, including hypertension, multiple sclerosis, cancer and infections. These findings provide a novel mechanism for the pathology of certain diseases and indicate that salt might serve as a target or potential therapeutic agent in different disease contexts. CONCLUSION: High salt has a profound impact on the differentiation, activation and function of multiple immune cells. Additionally, an HSD can modulate the development of various immune-regulated diseases.