Calcium ion (Ca2+) accumulation and excessive oxidative stress in the hippocampus and brain cortex have long been known as major contributors to the etiology of epilepsy. I have reviewed the role of Ca2+ signaling through cation channels and mitochondria-mediated oxidative stress on epilepsy in human and animals. A review of the relevant papers and results from recent studies were obtained from PubMed and the Science Citation Index. Current literature findings indicate that melatonin and agomelatine reduce activation of hippocampal transient receptor potential (TRP), glutamate receptors, and voltage-gated calcium channels that are critical for the development of abnormal Ca2+ homeostasis and oxidative stress and associated mitochondrial dysfunction. In addition, low doses of melatonin induce anticonvulsant action through increase of GABA levels in the hippocampus and brain cortex. The accumulating evidence implicates a modulator role of melatonin on excessive oxidative stress products, plus mitochondrial and Ca2+ dysregulations in epilepsy. The evidence indicates that modulation of oxidative stress and neuronal Ca2+ handling occurs through effects on TRP channels, suggesting an increasingly viable approach for therapeutic interventions against epilepsy.