Objective This study aimed to investigate the effects of mill type and process parameters on granule and tablet quality attributes during roller compaction and to develop a design space for optimizing granule flowability and tablet tensile strength. Significance Roller compaction improves granule flowability but can reduce tabletability. Mill type remains underexplored despite its potential impact on granule properties and downstream tablet performance. Methods Microcrystalline cellulose-based granules were prepared by roller compaction and milled using bar and knife rotors. The effects of screen size, mill speed, roll force, and mill type were evaluated using a Box–Behnken design. Granule size distribution, bed density, compressibility, flowability, granule shape, and tablet tensile strength were measured. Design space analysis was conducted using predefined criteria for angle of repose and tablet tensile strength. Results Mill type significantly interacted with process parameters, leading to distinct trends in granule size, density, compressibility, and flowability. Larger screen size and higher roll force produced coarser and denser granules, improving flowability. However, higher roll force reduced tablet tensile strength. Opposite effects of mill speed were observed between the two rotor types, which may be associated with differences in milling mechanism and material-retention behavior within the milling chamber. Design space analysis identified limited operating regions satisfying both flowability and tablet strength criteria, and the model-predicted conditions were experimentally verified. Conclusions Mill type was an important factor influencing roller compaction performance and should be considered during process optimization. The formulation- and equipment-specific design space enabled simultaneous optimization of granule flowability and tablet tensile strength.