Anisotropic transport properties have been assessed in a number of cuprate superconductors, providing evidence for a nematic state. We have recently shown that in ultra-thin YBa2Cu3O7−δ films, where nematicity is induced via strain engineering, there is a suppression of charge density wave scattering along the orthorhombic a-axis and a concomitant enhancement of strange metal behavior along the b-axis. Here we develop a microscopic model, that is based on the strong interaction between the substrate facets and the thin film, to account for the unconventional phenomenology. Based on the atomic force microscopy imaging of the substrates’ surface, the model is able to predict the absence (presence) of nematicity and the resulting transport properties in films grown on SrTiO3 (MgO) substrates. Our result paves the way to new tuning capabilities of the ground state of high-temperature superconductors by substrate engineering.