There is growing evidence for the efficacy of music, specifically Mozart’s Sonata for Two Pianos in D Major (K448), at reducing ictal and interictal epileptiform activity. Nonetheless, little is known about the mechanism underlying this beneficial “Mozart K448 effect” for persons with epilepsy. Here, we measured the influence that K448 had on intracranial interictal epileptiform discharges (IEDs) in sixteen subjects undergoing intracranial monitoring for refractory focal epilepsy. We found reduced IEDs during the original version of K448 after at least 30-s of exposure. Nonsignificant IED rate reductions were witnessed in all brain regions apart from the bilateral frontal cortices, where we observed increased frontal theta power during transitions from prolonged musical segments. All other presented musical stimuli were associated with nonsignificant IED alterations. These results suggest that the “Mozart K448 effect” is dependent on the duration of exposure and may preferentially modulate activity in frontal emotional networks, providing insight into the mechanism underlying this response. Our findings encourage the continued evaluation of Mozart’s K448 as a noninvasive, non-pharmacological intervention for refractory epilepsy.