Abstract: The hypothalamic-pituitary-adrenal (HPA) axis is involved in the pathophysiology of many neuropsychiatric disorders. Increased HPA axis activity can be observed during chronic stress, which plays a key role in the pathophysiology of depression. Overactivity of the HPA axis occurs in major depressive disorder (MDD), leading to cognitive dysfunction and reduced mood. There is also a correlation between the HPA axis activation and gut microbiota, which has a significant impact on the development of MDD. It is believed that the gut microbiota can influence the HPA axis function through the activity of cytokines, prostaglandins, or bacterial antigens of various microbial species. The activity of the HPA axis in schizophrenia varies and depends mainly on the severity of the disease. This review summarizes the involvement of the HPA axis in the pathogenesis of neuropsychiatric disorders, focusing on major depression and schizophrenia, and highlights a possible correlation between these conditions. Although many effective antidepressants are available, a large proportion of patients do not respond to initial treatment. This review also discusses new therapeutic strategies that affect the HPA axis, such as glucocorticoid receptor (GR) antagonists, vasopressin V1B receptor antagonists and non-psychoactive CB1 receptor agonists in depression and/or schizophrenia.