Metal-organic cages with well-defined interior cavities and tunable surface chemistry serve as attractive building blocks for new types of soft nanoporous materials. While a compositionally diverse repertoire of metal-organic cages exists, the vast majority feature highly symmetric cores. Here, we report a robust, generalizable synthetic route toward anisotropic copper paddlewheel-based cages with tunable pendant amide groups. An isostructural family with increasingly hydrophobic surface properties has been synthesized and characterized by single-crystal X-ray diffraction, gas sorption analysis, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and 1H NMR digestion experiments. The metal-organic cages reported here may enable a deeper study of how anisotropy influences the long-range structure and emergent function of soft nanoporous materials.