In this work, microstructure observation and thermo-mechanical property characterization of ion-irradiated Zr-0.5Sn-0.5Nb-0.3Fe-0.015Si alloys were addressed by both experimental measurements and theoretical analyses. In experiments, 6 MeV Au3+ irradiation was carried out for Zr alloys with the irradiation dose up to 30 displacements per atoms (dpa). Transmission electron microscopy (TEM) indicated the addition of solute elements could facilitate the formation of second phase particles (SPPs) like (Zr, Nb)2Fe, Zr(Nb, Fe)2 and Zr-Nb-Fe-Si precipitates in the unirradiated matrix, which were then transformed from the crystalline to amorphous state during the irradiation process. Moreover, it was indicated that there existed microband structures with different orientations inside the grains, and the actual irradiation depth had exceeded the value predicted by the SRIM simulation. The influence of irradiation-induced defects on the macroscopic mechanical behaviors of Zr alloys was characterized by both nano-indentation test (NIT) at 298 K and high-temperature nano-indentation test (HTNIT) at 573 K and 673 K. To theoretically address the hardness-indentation depth relations of ion-irradiated Zr alloys at elevated temperatures, a mechanistic model considering the underlying hardening mechanisms was developed. It was revealed that the irradiation hardening behavior was attributed to the contribution of irradiation-induced defects, while the decrease of hardness at elevated temperatures was ascribed to the weakening of all hardening mechanisms. In addition, with increasing indentation depth, the dominant hardening mechanisms changed from the contribution of irradiation-induced defects and geometrically necessary dislocations (GNDs) to those of statistically stored dislocations (SSDs).