ObjectiveTo observe the clinical efficacy of Xiao’er kang xian capsule added to anti-seizure medications (ASMs) in the treatment of children with refractory epilepsy and its influence on serum neuron-specific enolase (NSE) and cludter of differentiation 19+ (CD19+) levels. Methods A total of 60 children with refractory epilepsy were selected from the pediatric outpatient department and ward of Guangdong Provincial People's Hospital from February 2021 to June 2023. The study subjects were divided into two groups by numerical random method,with 30 cases in each group. The children with Xiao’er kang xian capsule added to the original treatment were the treatment group and the children without Xiao’er kang xian capsule added to the original treatment were the control group. The frequency, duration, EEG characteristics, adverse reactions and changes in serum NSE and CD19+ levels of the two groups were compared after treatment. Results Self-control before and after treatment in the treatment group: the frequency and duration of seizures were significantly reduced, with statistical difference (P<0.05). EEG discharge index in awake period and sleep period were significantly decreased, with statistical difference (P<0.05). After 6 months of treatment, comparison between the two groups of children: the seizure frequency of children in the treatment group was significantly decreased compared with the control group (P=0.03). There was a statistical difference (P<0.05), and the seizure duration in the treatment group was less than that in the control group (P=0.863), the clinical effective rate of treatment group 83.33% was higher than that of control group 63.33% (P=0.08), the effective rate of EEG in treatment group 80% was higher than that of control group 60% (P=0.091), serum NSE and CD19+ in treatment group were lower than that of control group, with no statistical difference (P>0.05). After 12 months of treatment, the frequency and duration of seizures in the treatment group were significantly decreased (P<0.05). The clinical efficacy and effectiveness of treatment group were significantly higher than that of control group (P=0.038). The incidence of adverse reactions in both groups was 16.67% (P>0.05). The effective rate of EEG in treatment group was significantly higher than that in control group (P=0.053). Serum NSE and CD19+ in treatment group were significantly lower than those in control group (P<0.05). ConclusionFor children with refractory epilepsy, the addition of Xiao’er kang xian capsule on the basis of the original treatment has obvious effect low adverse reaction and high safety. NSE and CD19+ can be used as monitoring indicators for the influence of the disease and prognosis evaluation during the treatment of children with epilepsy.