Anisotropic permeability of bentonite mixtures governs water flow regime in buffer materials such as landfill cover systems, cutoff walls, and high-level waste repositories. Because of its widespread application, a series of 48 permeability tests were conducted in this study on specimens prepared from bentonite-sand mixtures with three bentonite contents. The tests were run along both isotropic loading and unloading paths to explore the evolution of anisotropic ratio from three distinct fabric anisotropy states. Accordingly, a new cubic sample-type, large-scale triaxial permeameter was introduced and employed. The results revealed an enhancement of as-compacted anisotropy ratio from 1 to almost 7 with bentonite contents. The anisotropy ratio was suppressed with isotropic loading for 40% and 70% bentonite while it was enhanced for 10% bentonite content. Unloading was revealed to reduce the anisotropy of higher bentonite contents due to the enhancement of fissures along horizontal and vertical directions. The practical implication in terms of the long-term performance of a landfill liner with medium to high bentonite contents is that despite a 10- to 30-fold reduction in permeability with loading, the leachate flow would be less anisotropic compared with the initial condition as supported by a reduction in the anisotropy ratio up to 3.5.