Deep brain stimulation (DBS) is an important effective treatment for pharmacoresistant epilepsy, but its mechanism is still not clear. In clinical application, the possible effects and mechanisms DBS in treatment of epilepsy are different according to different stimulation parameters. We reviewed the mechanisms of DBS in different frequencies including high frequency and low frequency in the treatment of epilepsy, covering the inhibition or excitation of synaptic, pathological neuronal and network activity, pathological rhythms or oscillation and neurotransmitter systems. As the onset and progression of seizure, it’s more frequent accompanied with cognitive and psychiatric comorbidities in patients with epilepsy. We review the possible mechanism of DBS in treating epilepsy associated comorbidities including cognitive and memory disorders. With the further development of clinical application and basic research of DBS, the processing of clinical individualized therapy of DBS in epilepsy and evaluation of effects of DBS in associated comorbidities may contribute to extend the understanding of the mechanisms of DBS for epilepsy and associated comorbidities.