This paper is concerned with optimizing the fuel–air mixing processes that take place within the radial swirler slot of a dry low emission (DLE) combustion system. The aerodynamics of the flow within the slot is complex and this, together with the placement of the fuel holes with cross injection, controls the mixing of the fuel and air. Computational fluid dynamics (CFD) with the shear stress transport (SST) (k–) turbulence model was used for flow and mixing predictions within the radial swirler slot and for conducting a CFD-based design of experiments (DOE) optimization study, in which different parameters related to the fuel injection holes were varied. The optimization study was comprised of 25 orthogonal design configurations in the Taguchi L25 orthogonal array (OA). The test domain for the CFD, and its experimental validation, was a large-scale representation of a swirler slot from the Siemens proprietary DLE combustion system. The DOE study showed that the number of fuel holes, injection hole diameter, and interhole distance are the most influential parameters for determining optimal fuel mixing. Consequently, the optimized mixing configuration obtained from the above study was experimentally tested on an atmospheric test facility. The mixing patterns from experiments at various axial locations across the slot are in good agreement with the mixing predictions from the optimal CFD model. The optimized fuel injection design improved mixing compared with the baseline design by about 60%.