The influence of high pressure (~0–20 GPa) on the structural and microstructural parameters of zinc oxide, ZnO, was investigated using the X-ray powder diffraction. The information on unit cell parameters, crystallite size, and microstrainsunder both, compression and decompression was obtained using the Rietveld refinement. It was observed that the increase in pressure shifts the diffraction maxima towards higher Bragg angles, and induces a phase transition from hexagonal to cubic structure. The structure refinement revealed that the hexagonal structure of ZnO is more compressible in the c-direction, and that there is a linear decrease in the c/a ratio. The transition from hexagonal to cubic arrangement was accompanied by a sharp decrease in the volume of the ZnO unit cell by ~20%. It appears that the ratios d(100)/d(002) for the hexagonal and d(020)/d(220) for the cubic phase are highly correlated with the pressure changes - the ratio d(100)/d(002) increases linearly with the pressure before phase transition and deviates from the linear relationship in the transition zone, while the ratio d(020)/d(220) decreases slightly with the pressure after the phase transition. After the pressure drops from 17.92 GPa to 0 GPa, no reversible return of the cubic ZnO structure to the exclusively hexagonal arrangement was observed - the relative weight percentage of the cubic phase at 0 GPa is ~52%, while the hexagonal phase accounts for ~48%. The line profile analysis by Rietveld refinement showed the broadening of the diffraction maximaleading to the reduction of the crystallite size from 35 nm at atmosphere conditions to 18 nm at 17.92 GPa. On the other hand, the microstrains increased from 0.35% to 0.68% under the influence of mechanical pressure. Decompression from 17.92 GPa to 0 GPa showed a partially reversible effect on microstructural parameters - crystallite size increased from ~18 nm to ~30 nm, while microstrains decreased from 0.68% to 0.39%.These results are in accordance with the research published in the literature.