Mounting evidence underscores the pivotal role of immune-mediated and inflammatory mechanisms in mental disorders, significantly modulated by the neuroendocrine system. In conditions such as schizophrenia spectrum disorders (SSDs), affective disorders, and neurodegenerative disorders, inflammatory pathways have been identified. Notably, neuroendocrine pathways, like the hypothalamic–pituitary–adrenal (HPA) axis, play a substantial role in the body’s response to stress. The complex interplay between the immune and neuroendocrine systems profoundly impacts neuroplasticity. These three domains—psychopathology, inflammation, and neuroendocrine imbalance—reciprocally influence each other, forming shared pathophysiological foundations in both mental and physical disorders. Furthermore, social determinants wield a significant influence within this complex interplay. This chapter provides an overview of some of the most relevant mechanisms encompassing inflammation, the neuroendocrine system, and social determinants in health and disease. Understanding these insights enables a broader, more holistic approach to promoting physical and mental well-being. Additionally, it sets the stage for future individualized, subgroup-oriented therapeutic approaches.