People with epilepsy often have other comorbidities (such as depression, stroke, obesity, migraine, autism spectrum disorder, anxiety, bipolar disorder, attention deficit hyperactivity disorder, etc.). Approximately 50% of adults with active epilepsy have at least one Comorbidities of epilepsy. Epilepsy comorbidities are often associated with worse quality of life and prognosis. Vagus nerve stimulation (VNS) is a neuromodulation technique that relies on electrical stimulation and was approved by the Food and Drug Administration (FDA) in 1997 for the treatment of epilepsy. In the process of exploring the efficacy and mechanism of VNS in the treatment of epilepsy, an additional benefit was unexpectedly found, that is, VNS can meliorate symptoms of a variety of comorbidities. Since the FDA approved VNS for the treatment of depression in 2005, VNS has shown increasingly bright prospects in the treatment of comorbidities. In addition to the approved indications, including depression, stroke, obesity and migraine, VNS in other neuropsychiatric comorbidities have shown great potential. From invasive implantable VNS (iVNS) to non-invasive transcutaneous VNS (tVNS), studies on the benefits of VNS in the treatment of epilepsy and its Comorbidities are also evolving. This article reviews the progress of clinical treatment and mechanism of VNS in the treatment of epilepsy comorbidities in recent years, with the aim to provide the best treatment strategy for epilepsy patients and research basis for scientific researchers. At the same time, the parameter Settings of previous and latest clinical trials of VNS for the treatment of epilepsy comorbidity were summarized and analyzed to provide more references for the clinical application of VNS.