According to the International League Against Epilepsy (ILAE) definition, no structural abnormalities are present on a standard brain magnetic resonance image in genetic generalized epilepsy (GGE) patients. However, recent studies raise contradictory evidence with increasing use of quantitative magnetic resonance imaging techniques. Following PRISMA guidelines, a systematic, quantitative review was conducted using 28 peer-reviewed, case–control studies published after 1989. Furthermore, a meta-analysis with a random-effect model revealed differences in structural brain abnormalities between GGE patients and controls. Significant structural differences between GGE and healthy controls were observed with volume reductions in whole brain, thalamus, putamen, caudate, pallidum, and supplementary motor area. Furthermore, gray matter volume reduction in the right and left hemispheres, thalamus, and insula, and surface area reduction in the caudal anterior cingulate cortex were revealed, along with gray matter increase in the medial frontal gyrus. Due to methodological differences, findings should be interpreted with caution. Nevertheless, contrary to the ILAE definition, it would appear that structural brain abnormalities may be present in GGE patients. Findings are consistent with a hypothesis regarding the underlying involvement of the thalamocortical networks in the generation of generalized spike-wave discharges, but structural abnormalities appear to extend outside these regions to potentially involve attention and other cognitive domains.