Leber's hereditary optic neuropathy (LHON) is a rare, maternally inherited genetic disease caused by a mutation of mitochondrial DNA. Classical descriptions have highlighted structural abnormalities in various parts of patients' optic tracts; however, current studies have proved that changes also affect many cortical and subcortical structures, not only these belonging to the visual system. This study aimed at improving our understanding of neurophysiological impairments in LHON. First of all, we wanted to know if there were any differences between the health control and LHON subjects in the whole-brain source electroencephalography (EEG) analysis. Second, we wanted to investigate the associations between the observed results and some selected aspects of Leber's disease's clinical picture. To meet these goals, 20 LHON patients and 20 age-matched healthy control (HC) subjects were examined. To investigate the electrophysiological differences between the HC and LHON groups, a quantitative analysis of the whole-brain current source density was performed. The signal analysis method was based on scalp EEG data and an inverse solution method called low-resolution brain electromagnetic tomography (eLORETA). In comparison with the healthy subjects, LHON participants showed significantly decreased neuronal activity in the alpha and gamma bands; more specifically, in the alpha band, the decrease was mainly found in the occipital lobes and secondary visual cortex, whereas, in the gamma band, the reduced activity occurred in multiple cortical areas. Additionally, a correlation was found between the alpha band activity of the right secondary visual cortex and the averaged thickness of the right retinal nerve fiber layer in the LHON participants. Our study suggests that LHON is associated with widespread cortical de-activation, rather than simply abnormalities of structures constituting the visual system.