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It is well known that in the high-temperature superconductor YBa2Cu3O7-x (YBCO), oxygen vacancies (VO) control the carrier concentration, its critical current density and transition temperature. In this work, it is revealed that VO also allow the accommodation of local strain fields caused by large-scale defects within the crystal. We show that the nanoscale strain associated with Y2Ba4Cu8O18 (Y124) intergrowths—that are common defects in YBCO—strongly affect the venue and concentration of VO. Local probe measurements in conjunction with density-functional-theory calculations indicate a strain‐driven reordering of VO from the commonly observed CuO chains towards the bridging apical sites located in the BaO plane and bind directly to the superconducting CuO2 planes. Our findings have strong implications on the physical properties of the YBCO, as the presence of apical VO alters the transfer of carriers to the CuO2 planes and creates structural changes that affect the Cu-O bonds in the superconducting planes. In addition, the revelation of apical VO also has implications on modulating critical current densities and enhancing vortex pinning.