Objective To investigate the effect of ketogenic diet therapy combined with antiepileptic drugs on seizure frequency and serum monoamine neurotransmitters in patients with intractable epilepsy. Methods A total of 72 children with intractable epilepsy who were admitted to Department of Neurology in our hospital from January 2016 to February 2018 were enrolled. All children were given at least 3 months of ketogenic diet therapy on the basis of the treatment with antiepileptic drugs. After 3, 6, and 12 months of treatment, seizure frequency was statistically analyzed and electroencephalography (EEG) was used to evaluate brain discharge control. After 6 months of treatment, Wechsler Intelligence Scale for Children was used to evaluate cognitive function, and event-related potential P300 and serum levels of norepinephrine (NE), dopamine (DA), and 5-hydroxytryptamine (5-HT) were measured. Results All children were followed up, and the treatment was maintained 3 months for 72 children, 6 months for 60 children, and 12 months for 38 children. The effective control rates of clinical seizure were 40.3%, 50.0%, and 55.3%, respectively, after 3, 6, and 12 months of ketogenic diet therapy, and the complete seizure control rates were 2.8%, 18.3%, and 21.1%, respectively. The effective rates of brain wave reduction were 50.0%, 68.3%, and 76.3%, respectively. After 6 months of treatment, there were no significant changes in the scores of verbal intelligence quotient, performance intelligence quotient, and full-scale intelligence quotient (P>0.05), and the children had a significant reduction N2PL and significant increases in P3 amplitude and serum levels of the neurotransmitters such as NE, DA, and 5-HT (P<0.05). Conclusions Ketogenic diet combined with antiepileptic drugs is effective in the treatment of intractable epilepsy and can not only reduce seizure frequency but also improve children's cognitive function, possibly by the regulation of neurotransmitters.