Abstract Ion irradiation offers a promising strategy to emulate the irradiation damage induced by energetic neutrons. However, the characterization of the mechanical properties of ion-irradiated materials is not easy considering the limited irradiation depth and inhomogeneous distribution of irradiation-induced defects. Over the last decades, nano-indentation has been recognized as a valid technique to investigate the localized mechanical responses at micro-scale. Therefore, the combination of ion irradiation and nano-indentation has been extensively developed in recent years to study the mechanical behaviors of nuclear structural materials with irradiation effect. In this review, current developments of experimental observations, numerical simulations and theoretical models are summarized concerning both microstructural evolution and macroscopic deformation. Corresponding analysis and discussion could help obtain a sophisticated comprehension of the fundamental deformation mechanisms resulting in mechanical degradation of ion-irradiated materials, and further assist the development of next-generation nuclear structural materials.