Depression is the most common mental complication in patients with epilepsy. The high prevalence of epilepsy combined with depression suggests that there may exist potential co-morbid mechanisms between them. Synaptic plasticity and regeneration of neurons abnormality play important roles in the occurrence of epilepsy combined with depression. Changes in neuronal synaptic plasticity are closely related to abnormal changes in neural structure, abnormal neural networks and expressions of various synaptic proteins. Changes in synaptic plasticity and abnormal regeneration play important roles in the pathogenesis of epilepsy and depression. This paper summarizes the relation between epilepsy combined with depression and neuronal synaptic plasticity.