FeCrV multi-component alloys (MCAs) with trace amounts of Cu or Ti, synthetized via mechanical alloying and spark plasma sintering, have the characteristics of nanocrystalline and nano-precipitates, which contribute to their excellent mechanical properties at room temperature. The high thermal stability of nanostructure and exceptional irradiation resistance are of great significance for evaluating their potential advantages as advanced nuclear energy materials. In the present study, the response of structural stability and mechanical properties to the doping of Cu0.05 and Ti0.2 (at%) in FeCrV under series of annealing temperatures and durations was investigated systematically. FeCrVCu0.05 shows the satisfactory structure and performance stability until 600 °C for 30 h mainly due to the good thermal stability of Cu nano-precipitates (∼13 nm) and nanocrystalline (∼367 nm). In contrast, the excessive Laves phase of Fe2Ti appeared in FeCrVTi0.2 under the same annealing condition, exerting a detrimental impact on its high-temperature performance. Brittle FeV intermetallic compounds formed in both alloys at 800 °C for 5 h. Additionally, the irradiation resistance was evaluated by the sequential (Fe2++H+)-He+ ions implantation at 450 °C. The two alloys exhibit comparable resistance to irradiation hardening, probably attributed to their similar sink strength though the dominant sink is different. Electrical properties, thermal conductivity, Young's modulus and corrosion resistance of the two alloys were also obtained. A comparative analysis of the different effects of the doping of Cu and Ti was conducted. Collectively, some relevant experimental data on FeCrV-based MCAs was supplemented for a more comprehensive understanding of this family. This work may help to offer a feasible basis for further optimization of new MCAs.