Global burden of diseases (GBD) includes non-communicable conditions such as cardiovascular diseases, cancer and chronic obstructive pulmonary disease. These share important behavioral risk factors (e.g., smoking, diet) and pathophysiological contributing factors (oxidative stress, inflammation and excessive sympathetic activity). This article wishes to introduce to medicine and public health a new paradigm to predict, understand, prevent and possibly treat such diseases based on the science of neuro-immunology and specifically by focusing on vagal neuro-modulation. Vagal nerve activity is related to frontal brain activity which regulates unhealthy lifestyle behaviors. Epidemiologically, high vagal activity, indexed by greater heart rate variability (HRV), independently predicts reduced risk of GBD and better prognosis in GBD. Biologically, the vagus nerve inhibits oxidative stress, inflammation and sympathetic activity (and associated hypoxia). Finally, current non-invasive methods exist to activate this nerve for neuro-modulation, and have promising clinical effects. Indeed, preliminary evidence exists for the beneficial effects of vagal nerve activation in diabetes, stroke, myocardial infarction and possibly cancer. Thus, we propose to routinely implement measurement of HRV to predict such GBD in populations, and to test in randomized controlled trials effects of non-invasive vagal nerve activation on prevention and treatment of GBD, reflecting possible neuro-modulation of health.