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Iinvestigations in healthy humans have highlighted an overall good correspondence between functional and structural connectivity. However, recent studies examining congenital or surgical alteration of the corpus callosum have produced conflicting results that challenge this view. Here we used high-resolution DTI and fMRI to probe structural and functional brain connectivity in BTBR mice, an acallosal strain widely used to mimic autism-like symptoms. We provide evidence of adaptive structural and functional cortico-cortical connectivity together with the presence of severely impaired antero-posterior and subcortical functional correlations. Our results highlight a complex region-dependent interplay between function and structure in congenital acollosal brains.