While the efficacy of vagus nerve stimulation (VNS) to reduce seizures and improve comorbidities associated with pharmacoresistant epilepsy including mood as well as quality of life is clinically proven, the exact mechanism of VNS remains unclear. VNS exerts antiepileptic or anti-epileptogenic effect possibly through i) neuromodulation of release of noradrenaline from locus coeruleus; ii) induced profound changes in brain blood flow; iii) immunomodulation or anti-neuroinflammation; iv) change EEG brain functional connectivity; v) modification of the proteome of excitatory synapses of amygdaloid/piriform cortex; vi) modulation of adenosine system and DNA methylation. Beyond epilepsy, VNS is also under investigation for the treatment of epilepsy associated comorbidities including cognitive comorbidities and psychiatric comorbidities. Of importance, progression in VNS clinical efficacy over time suggests an underlying disease-modifying neuromodulation, which is an emerging field in pharmacoresistant epilepsy. With bidirectional potential clinical efficacy of VNS in epilepsy, a prototype neuropsychiatric illness, further research on the solid mechanisms of VNS for epilepsy and associated comorbidities is encouraging.