〔Abstract〕 Objective To analyze the clinical efficacy of phenobarbital combined with oxcarbazepine in the treatment of refractory epilepsy. Methods A total of 68 patients with intractable epilepsy admitted to Xiamen Haicang Hospital from February 2020 to January 2022 were selected and divided into control group (oxcarbazepine treatment) and observation group (phenobarbital combined with oxcarbazepine treatment) according to the random number table method, with 34 cases in each group. The clinical efficacy, seizures, Montreal cognitive assessment (MoCA) score, electroencephalogram (EEG), serum neurotransmitters and incidence of adverse reactions were compared between the two groups. Results The total effective rate of observation group was 94.12 %, higher than 73.53 % of the control group, and the difference was statistically significant (P < 0.05). After treatment, the number of seizures in the observation group was lower than that in the control group, and the MoCA score was higher than that in the control group, and the differences were statistically significant (P < 0.05). After treatment, the power of α and β bands in the observation group were higher than those in the control group, and the power of δ and θ bands were lower than those in the control group, and the differences were statistically significant (P < 0.05). After treatment, the levels of central nervous specific protein (S100-β) and myelin basic protein (MBP) in the observation group were lower than those in the control group, and the levels of neuropeptide Y (NPY) and brain-derived neurotrophic factor (BDNF) in the cerebrospinal fluid were higher than those in the control group, and the differences were statistically significant (P < 0.05). Conclusion Compared with oxcarbazepine alone, phenobarbital combined with oxcarbazepine can improve the treatment effect of refractory epilepsy patients, improve their EEG indicators and cognitive function.