Neurodevelopmental disorders are complex diseases with genetic and environmental factors shaping brain architecture. Here we undertook a proof of concept study to investigate brain structure using a glass-brain clearing and 3D-mapping workflow at high-resolution. Whole brain and sub-structure analysis included the genetic developmental and epileptic encephalopathy mouse model of Dravet syndrome (DS). In addition, we included the Black and Tan BRachyury (BTBR) mouse strain, which has acknowledged major and minor structural anomalies. Ex vivo P16 mouse brains were cleared using a modified solvent-based clearing method. The high-quality autofluorescence signal from light-sheet imaging provided unambiguous anatomical feature determination including the barrel-like regions of the cortex and absence of corpus callosum in BTBR mice. BTBR volume estimates were consistent with previous reports showing reduced hippocampal commissure volume. An automated image registration and statistical analysis pipeline was used to compare the control and DS model groups. Glass-brain images were registered to the scalable Allen Brain Atlas and annotations transformed into native space, with 20 μm isotropic voxels. Overall, glassbrain mapping provided a high-resolution measure of the premature mouse brain anatomy. We report novel structural changes in the DS model, which are consistent with cognitive and behavioural co-morbidities reported in this neurodevelopmental disease model.