The aim of this study was to investigate whether a different and abnormal corneal profile is present in Down syndrome (DS) by personalized three-dimensional (3D) modelling. This single-centre cross-sectional study included 43 patients with DS (43 eyes) and 58 age-sex-matched control subjects (58 eyes) with normal karyotype and topography. Refraction, central corneal thickness (CCT), aberrations (high-order, coma and spherical), asphericity and morphogeometric/volumetric parameters based on a 3D corneal model that was generated from raw topographical data were evaluated. Deviation of anterior/posterior apex (Dapexant/Dapexpost) and thinnest point (Dmctant/Dmctpost) from corneal vertex, anterior/posterior surface area (Aant/Apost), sagittal area passing through the anterior/posterior apex (Aapexant/Aapexpost) and thinnest point (Amctpost), total corneal volume (Vtotal) and volumetric progression for each 0.05 mm step of the radius value centred to the thinnest point (VOLMCT) and anterior/posterior apex (VOLAAP/VOLPAP) comprised the morphogeometric/volumetric parameters. In the DS group, 58.1% of the eyes presented abnormal topography. High-order and coma aberrations, asphericity, Dapexant, Aant, Apost and Aapexant were significantly higher, whereas CCT, Aapexpost, Amctpost, Vtotal, VOLAAP, VOLPAP and VOLMCT were lower in the DS group than in the control group (p < 0.05). Dapexpost did not differ between the groups (p > 0.05). This study demonstrates that corneas of the subjects with DS are different and more aberrated than those of normal age- and sex-matched non-DS controls. Anterior corneal apex appears to be displaced in DS even with normal topography, while posterior apex seems stable although topography is abnormal. These findings may help to modify our approach in the diagnosis of keratopathy in subjects with DS.