The aim of this work is to investigate the effect of high-temperature neutron irradiation on the mechanical properties of single-crystal tungsten W(100) studied by mechanical testing and modelling. Neutron irradiation up to 0.12 displacements per atom was performed at 600, 800, 900 and 1200°C in the Belgium material test reactor BR2 at SCK•CEN in Mol. The mechanical properties of the irradiated tungsten were assessed by impulse excitation and depth-sensing indentation measurements. The values of Young's modulus, shear modulus and Poisson ratio are not affected by the irradiation. The mean hardness of the irradiated tungsten increases by 48, 45, 46, and 34 % after irradiation at 600, 800, 900 and 1200 °C, respectively. The results obtained by the instrumented hardness tests were used as input for the finite element method model, applied to deduce the contributions coming from the neutron irradiation defects to the plastic deformation upon the indentation process, which include the impediment of gliding dislocations by sessile defects and modification of surface morphology due to the inhibited strain hardening ability through the dislocation-defect interaction. The validation of the fitted constitutive laws was realized by the crystal plasticity finite element method (CP-FEM) model, which was applied to simulate the indentation load-depth curves with certain assumptions on the irradiation-induced microstructure and calculate the distribution of stress under the indenter to investigate the extension of the plastic zone in the process of the indentation.