Type 2 diabetic mellitus (T2DM) is a common chronic disease and a substantial risk factor of other fatal illnesses. At its core is insulin resistance, where chronic low-level inflammation is among its main causes. Thus, it is crucial to modulate this inflammation. This review paper provides scientific neuroimmunological evidence on the protective roles of the vagal nerve in T2DM. First, the vagus inhibits inflammation in a reflexive manner via neuroendocrine and neuroimmunological routes. This may also occur at the level of brain networks. Second, studies have shown that vagal activity, as indexed by heart-rate variability (HRV), is inversely related to diabetes and that low HRV is a predictor of T2DM. Finally, some emerging evidence shows that vagal nerve activation may reduce biomarkers and processes related to diabetes. Future randomized controlled trials are needed to test the effects of vagal nerve activation on T2DM and its underlying anti-inflammatory mechanisms.