Using first-principles and analytical potential atomistic simulations, production of defects in epitaxial graphene (EG) on SiC upon ion irradiation for ion types and energies accessible in helium-ion microscope is studied. Graphene-SiC systems consisting of the buffer (zero) graphene layer and SiC substrate, as well as one (monolayer) and two (bilayer) additional graphene layers, are focused on. The probabilities for single, double, and more complex vacancies to appear upon impacts of energetic ions in each graphene layer as functions of He-and Ne-ion energies are calculated and the data are compared with those obtained for freestanding graphene. The results indicate that the role of the substrate is minimal for He-ion irradiation with energies above 5 keV, which can be associated with a low sputtering yield from this system upon ion irradiation, as compared with the common Si/SiO 2 substrate. In contrast, SiC substrate has a significant effect on defect production upon Ne-ion irradiation. The results can serve as a guide to the experiments on ion irradiation of EG to choose the optimum ion beam parameters for defect-mediated engineering of such systems, for example, for creating nucleation centers to grow other 2D materials, such as h-BN, on top of the irradiated EG.