Autonomic dysfunction and chronic inflammation contribute to the pathogenesis and progression of several cardiovascular diseases (CVD), such as heart failure with preserved ejection fraction, atherosclerotic CVD, pulmonary arterial hypertension, and atrial fibrillation. The vagus nerve provides parasympathetic innervation to the heart, vessels, and lungs, and is also implicated in the neural control of inflammation through a neuroimmune pathway involving the spleen. Stimulation of the vagus nerve (VNS) can in principle restore autonomic balance and suppress inflammation, with potential therapeutic benefits in these diseases. Although VNS ameliorated CVD in several animal models, early human studies have demonstrated variable efficacy. The purpose of this review is to discuss the rationale behind the use of VNS in the treatment of CVD, to critically review animal and human studies of VNS in CVD, and to propose possible means to overcome the challenges in the clinical translation of VNS in CVD.