Background: Greater variability of neuronal signalling, measured as the standard deviation of the blood oxygen dependent signal (BOLDSD), relates to information processing capacity. Resting-state functional magnetic resonance imaging was used to determine differences in BOLDSD between children with and without epilepsy. Methods: We studied 24 controls (mean age 8.52 ± 1.35 years) and 18 patients (mean age 11.5 ± 3.4 years) with medically refractory epilepsy that underwent imaging for preoperative planning.Standard preprocessing steps (FSL v6.0, FMRIB) were followed and AAL atlas was used. Whole-brain two sample t-tests were used for group comparisons and significance was set at p <0.05 FDR-corrected. Results: Children with epilepsy showed significantly lower BOLDSD in left inferior and middle temporal gyri (p < 0.001), right caudate nucleus (p < 0.01), cuneus (p < 0.001), and fusiform gyrus (p < 0.001), and significantly increased BOLDSD bilaterally in inferior occipital gyri (p < 0.0001). There were no significant differences when comparing whole-brain BOLDSD values. Conclusions: Neuroplastic changes in epilepsy may depend on an optimal amount of internal neural variability driven by the identified key regions. Certain temporal and occipital regions may underlie neural processing differences in children with epilepsy. Further studies may correlate these findings with behavioral testing.