Substrate clamping and inter-domain pinning limit movement of non-180° domain walls in ferroelectric epitaxial films thereby reducing the resulting piezoelectric response of ferroelectric layers. Our theoretical calculations and experimental studies of the epitaxial PbZrxTi1–xO3 films grown on single crystal SrTiO3 demonstrate that for film compositions near the morphotropic phase boundary it is possible to obtain mobile two-domain architectures by selecting the appropriate substrate orientation. Transmission electron microscopy, X-ray diffraction analysis, and piezoelectric force microscopy revealed that the PbZr0.52Ti0.48O3 films grown on (101) SrTiO3 substrates feature self-assembled two-domain structures, consisting of two tetragonal domain variants. For these films, the low-field piezoelectric coefficient measured in the direction normal to the film surface (d33) is 200 pm V–1, which agrees well with the theoretical predictions. Under external AC electric fields of about 30 kV cm–1, the (101) films exhibit reversible longitudinal strains as high as 0.35 %, which correspond to the effective piezoelectric coefficients in the order of 1000 pm V–1 and can be explained by elastic softening of the PbZrxTi1–xO3 ferroelectrics near the morphotropic phase boundary.