Mozart's Sonata for Two Pianos in D Major (K448) is a classic double piano work. This study investigated its effect on children with epilepsy (EP) and analyzed the changes in electroencephalography (EEG) among children on the basis of acoustic quality. The clinical data of 150 children with EP in the Affiliated Hospital (Group) of Putian University from March 2020 to March 2023 were retrospectively analyzed. They were divided into group A (n = 73, antiepileptic drug therapy) and group B (n = 77, antiepileptic drug therapy + Mozart K448) in accordance with the treatment methods. The seizure frequency, frequency of epileptic discharges (EDs), and Quality of Life in Childhood Epilepsy Questionnaire-16 in both groups were compared before and after treatment. The changes in EEG before, during, and after music appreciation were observed. The effects of the acoustic characteristics (rhythm, root mean square value, roughness, and spectral flux) of Mozart K448 on EDs in children were explored. After treatment, group A had a higher seizure frequency (P < 0.001), a higher frequency of EDs (P < 0.05), and significantly lower scores of cognition and emotion than group B (P < 0.001), without significant difference in the scores of social function and physical function (P > 0.05). The frequency of EDs before music appreciation was significantly higher than that during music appreciation (P < 0.01). Spearman correlation analysis showed that the rhythm, spectral flux, and roughness in Mozart K488 were related to the decrease in EDs among children with EP (P < 0.001). This study confirmed the application effect of Mozart K448 in children with EP. Mozart K448 can decrease the seizure frequency, reduce the ED occurrence, and improve the quality of life. The acoustic characteristics of K448 may be the reason for improving EP in children.