We combine quantum-chemical calculations and molecular dynamics simulations to consider aqueous ion flow across non-axisymmetric nanopores in monolayer graphene and MoS₂. When the pore-containing membrane is subject to uniaxial tensile strains applied in various directions, the corresponding permeability exhibits considerable directional dependence. This anisotropy is shown to arise from directed perturbations of the local electrostatics by the corresponding pore deformation, as enabled by the pore edge geometries and atomic compositions. By considering nanopores with ionic permeability that depends on the strain direction, we present model systems that may yield a detailed understanding of the structure–function relationship in solid-state and biological ion channels. Specifically, the observed anisotropic effects potentially enable the use of permeation measurements across strained membranes to obtain directional profiles of ion–pore energetics as contributed by groups of atoms or even individual atoms at the pore edge. The resulting insight may facilitate the development of subnanoscale pores with novel functionalities arising from locally asymmetric pore edge features.