Ni-based fcc alloys are frequently used as critical structural materials in nuclear energy applications. Despite extensive studies, fundamental questions remain regarding point defect migration and solute segregation as a function of grain boundary character after irradiation. In this study, a coupled experimental and modeling approach is used to understand the response of grain boundary character in a model Ni–5Cr alloy after high temperature heavy-ion irradiation. Radiation-induced segregation and void denuded zones were experimentally examined as a function of grain boundary character, while a kinetic rate theory model with grain boundary character boundary conditions was used to theoretically model Cr depletion in the alloy system. The results highlight major variations in the radiation response between the coherent and incoherent twin grain boundaries, but show limited disparity in defect sink strength between random low- and high-angle grain boundary regimes.