Control and design of native defects in semiconductors are extremely important for industrial applications. Here, we investigated the effect of external hydrostatic pressure on the redistribution of native defects and their impact on structural phase transitions and photoconductivity in ZnO. We investigated morphologically distinct rod- (ZnO-R) and flower-like (ZnO-F) ZnO microstructures where the latter contains several native defects namely, oxygen vacancies, zinc interstitials and oxygen interstitials. Synchrotron X-ray diffraction reveals pressure-induced irreversible phase transformation of ZnO-F with the emergence of a hexagonal metallic Zn phase due to enhanced diffusion of interstitial Zn during decompression. In contrast, ZnO-R undergoes a reversible structural phase transition displaying a large hysteresis during decompression. We evidenced that the pressure-induced strain and inhomogeneous distribution of defects play crucial roles at structural phase transition. Raman spectroscopy and emission studies further confirm that the recovered ZnO-R appears less defective than ZnO-F. It resulted in lower photocurrent gain and slower photoresponse during time-dependent transient photoresponse with the synergistic application of pressure and illumination (ultra-violet). While successive pressure treatments improved the photoconductivity in ZnO-R, ZnO-F failed to recover even its ambient photoresponse. Pressure-induced redistribution of native defects and the optoelectronic response in ZnO might provide new opportunities in promising semiconductors.