Discrete element modelling (DEM) is commonly used for particle-scale modelling of granular or particulate materials. Creation of a DEM model requires the specification of a number of micro-structural parameters, including the particle contact stiffness and the interparticle friction. These parameters cannot easily be measured in the laboratory or directly related to measurable, physical material parameters. Therefore, a calibration process is typically used to select the values for use in simulations of physical systems. This paper proposes optimising the DEM calibration process by applying the Taguchi method to analyse the influence of the input parameters on the simulated response of powder agglomerates. The agglomerates were generated in both two and three dimensions by bonding disks and spheres together using parallel bonds. The mechanical response of each agglomerate was measured in a uniaxial compression test simulation where the particle was compressed quasi-statically between stiff, horizontal, frictionless platens. Using appropriate experimental designs revealed the most important parameters to consider for successful calibration of the 2D and 3D models. By analysing the interactive effects, it was also shown that the conventional calibration procedure using a “one at a time” analysis of the parameters is fundamentally erroneous. The predictive ability of this approach was confirmed with further simulations in both 2D and 3D. This demonstrates that a judicious strategy for application of Taguchi principles can provide a sound and effective calibration procedure.