Loneliness and social isolation are pressing societal concerns with many downstream ramifications on mental and physical health. The prevalence and burden of these issues have become even more intense in the wake of the COVID-19 pandemic, elevating them to the status of a public health epidemic as declared by Dr. Vivek Murthy, U.S. Surgeon General. While the consequences are now well-established, understanding how social isolation and loneliness translate into ill health requires an integrated view of central and peripheral physiological mechanisms. The present review looks across allostatic systems to identify psychophysiological mechanisms through which loneliness and social increase health risk, framing them within the context of Allostatic Theory. Specifically, we discuss neurobiological, neuroendocrinological, immunological, and cardiovascular responses as well as interactions among these pathways and future directions in this space. Neurobiological correlates span structure, function, and neuropeptides, notably in regions such as the prefrontal cortex and limbic areas, and networks including the attentional, visual, and default mode networks. These neurobiological changes interweave with dysregulated hormonal responses such as elevated cortisol, and weakened immune function marked by heightened inflammatory markers. Cardiovascular responses, including increased blood pressure and arterial stiffness, further compound the impact of loneliness and social isolation on physiology. The interplay among these allostatic systems collectively drives the progression of chronic illnesses and contributes to heightened morbidity and mortality. By synthesizing evidence across these domains, this integrative review highlights the need for a comprehensive understanding of the molecular mechanisms linking loneliness and social isolation to various psychophysiological bases, as well as the development of targeted interventions to address the adverse effects of social stress on health.