In order to obtain a fundamental understanding of the phenomena accompanying thermomechanical fatigue of Cu metallization used in power electronics, as well as the resulting deterioration of electric properties, there is a need to assess intragranular microstructure and strain evolution within individual Cu grains and near grain boundaries. Here, synchrotron dark field X-ray microscopy (DFXM) is used to characterize as-deposited and 5 × 104 times thermally-cycled 20 µm thick Cu films. The cycling was performed using a dedicated test chip in the range of 100–400 °C applying a heating rate of 106 K/s. The thermomechanical treatment results in severe shear deformation of Cu grains, film surface roughening, gradual grain microstructural refinement, the emergence of microscopic voids preferably at high angle grain boundaries (HAGBs) and finally in the voids' percolation, as revealed by in-situ and ex-situ scanning electron microscopy. DFXM provides experimental evidence that mosaicity of Cu grains, residual tensile and compressive elastic strain concentrations and full width at half maximum of Cu 111 reflections increase simultaneously in the vicinity of the HAGBs. The latter is interpreted as resulting from vacancy condensation in front of the HAGBs, after dislocations have moved across cycled grains and partly annihilated. Moreover, the observed HAGB decohesion and gradual void formation are correlated with the supposed hardening of regions near HAGBs, which thus lose their ductility during cyclic elasto-plastic deformation. The results are complemented with the ex-situ X-ray nanotomography data, which document the voids' percolation across the film's thickness with a “crack” width of up to ∼2 µm. In general, the study identifies the inhomogeneous intragranular microstructural refinement and a gradual condensation of structural defects near HAGBs as driving forces for void formation in thick Cu metallizations during fast thermo-mechanical fatigue.