<p>Interfacial strain engineering by controlling lattice mismatch holds implications for both fundamental studies and technological applications of heterostructured nanomaterials. However, defining its role remains challenging because the type, magnitude, and spatial distribution of strain are difficult to regulate at the nanoscale. Here, we establish a controllable model system to regulate interfacial lattice strain in lanthanide-doped core-shell-shell nanolattices by tuning lanthanide composition and shell deposition rate. We show that lattice mismatch governs lanthanide migration across heterointerfaces, thereby dictating crystal growth and optical properties. In hexagonal-phase NaErF₄@NaYF₄@NaLnF₄ nanolattices, when the lattice mismatch exceeds 5.1%, lanthanide ions migrate by up to 13 nm from the core into the shell along the &lt; 1000&gt; crystallographic direction. Mechanistic studies reveal that large interfacial strain not only promotes anisotropic shell growth by triggering preferential deposition of shell precursors onto specific crystal surfaces but also facilitates the formation of lanthanide vacancies at the core-shell interface. These findings identify interfacial strain as a key regulator of ion diffusion and structural evolution in heterostructured nanocrystals, providing a design principle for constructing heterostructures with spatially confined active ions for applications in bioimaging, nanocatalysis, and quantum information.</p>