In mechanical deformation of crystalline materials, the critical resolved shear stress (CRSS;
τCRSS ) is the stress required to initiate movement of dislocations on a specific plane. In plastically anisotropic materials, such as Mg, τCRSS for different slip systems differs greatly, leading to relatively poor ductility and formability. However, τCRSS for all slip systems increases as the physical dimension of the sample decreases to approach eventually the ideal shear stresses of a material, which are much less anisotropic. Therefore, as the size of a sample gets smaller, the yield stress increases and τCRSS anisotropy decreases. Here, we use in situ transmission electron microscopy mechanical testing and atomistic simulations to demonstrate that τCRSS anisotropy can be significantly reduced in nanoscale Mg single crystals, where extremely high stresses (∼2 GPa) activate multiple deformation modes, resulting in a change from basal slip-dominated plasticity to a more homogeneous plasticity. Consequently, an abrupt and dramatic size-induced “brittle-to-ductile” transition occurs around 100 nm. This nanoscale change in the CRSS anisotropy demonstrates the powerful effect of size-related deformation mechanisms and should be a general feature in plastically anisotropic materials.