•The three regions of the welded joint present different hardening behavior under the same irradiation condition.•He bubbles are the main reason for the different hardening behavior of welded joints after He ions irradiation.•The different structures of intrinsic dislocation lines in the welded joints affect the nucleation and growth of He bubbles in the grain. Irradiation damage due to helium embrittlement impacts the safety and integrity of welded structural materials in power reactors. To understand this helium effect, in this study, GH3535 welded joints were irradiated at 650°C with 500 keV He ions at various doses to investigate the effects of He bubbles on the weld, heat-affected zone (HAZ), and base metal. The three regions exhibited different hardening behaviors. The hardness of the weld and HAZ after irradiation increased proportionately with the ion dose. The hardness of the base metal gradually saturates at a dose of 2 × 1016 ions/cm2. At the highest dose (1 × 1017 ions/cm2), the degree of hardening in the three regions was as follows: weld (92.9%) > HAZ (91.3%) > base metal (72.7%). The microstructures of the samples revealed that the mean diameters of the He bubbles in the weld, HAZ, and base metal were approximately 2.74, 2.80, and 2.36 nm, respectively, with corresponding number densities of 15.4 × 1023, 10.8 × 1023, and 9.69 × 1023 m−3. Furthermore, the yield strength increment was calculated using the dispersed barrier hardening model, which suggested that the helium bubbles played an important role in the different hardening behavior of the welded joint. The nucleation and growth of helium bubbles was influenced by the structures of the intrinsic dislocations in the weld, HAZ, and base metal. The different helium bubble microstructures are the main reason for variations in the hardening behavior of welded joints under identical conditions Display omitted .