Abstract: Hydrogen irradiation profoundly changes the microstructure and morphological characteristics of tungsten, ultimately resulting in the modifications to its mechanical properties. Unfortunately, the specific mechanisms through which hydrogen irradiation influences the mechanical behavior of tungsten have not been clearly elucidated. Therefore, this study aims to further improve the understanding of the impact of hydrogen irradiation on the mechanical responses and its microstructure dependence in tungsten by employing two advanced techniques: nano-indentation experiments and Molecular dynamics (MD) simulations. The experimental findings revealed that deuterium (D) exposure decreased the maximum shear stress required for the incipient plasticity and led to the occurrence of multiple pop-ins. Particularly noteworthy was the most remarkable change in mechanical behaviors observed prominently in the recrystallized tungsten after D exposure. The microstructure dependence of irradiation-induced change in mechanical responses was investigated by two series of MD simulation, indentation and dislocation glide simulation, focusing on the independent effects of each irradiation-induced defect type (interstitial, substitutional, vacancy, vacancy-hydrogen (Vac-H) cluster, void-hydrogen (Vo-H) cluster) on dislocation activities. Based on the MD simulations, it was eventually revealed that Vo-H clusters were the most influential agent affecting dislocation activities. They not only lowered the pop-in stress by heterogeneous dislocation nucleation but also caused strain serration by a continuous pinning/unpinning process during dislocation glide. Consequently, we concluded that the dominant presence of d-induced Vo-H clusters facilitated the onset of plastic yielding and led to multiple pop-in phenomena in recrystallized tungsten, whereas inserted hydrogen caused minimal change in mechanical responses by interacting with pre-existing dislocation in cold-rolled tungsten.