Some directly compressible powders and granules can be combined to prepare tablets of optimum qualities. The aim of this research work was to formulate, optimize and characterize diclofenac sodium tablets using varying concentrations of microcrystalline cellulose (MCC) powder and lactose granules (DC excipients), and maize starch powder. Diclofenac tablets were prepared by direct compression using a simplex lattice (centroid) optimization design involving maximum, mid-point and minimum levels of MCC, lactose granules and maize starch. The powder mixtures were evaluated for micromeritic properties, which include bulk and tapped densities, Hausner’s quotient, Carr’s compressibility index, while the tablets were assessed for weight uniformity, crushing strength, friability, disintegration time and dissolution rate. The friability and crushing strength of the tablets batches were within the ranges of 0.3-1.7% and 1.4-8.4 KgF, respectively. Powder blends containing low MCC, low lactose granules and high starch levels and also, combinations comprising low MCC and mid-point lactose granules and starch concentrations showed the lowest disintegration times and the highest drug release. Special cubic and quadratic equations were derived for the prediction of diclofenac release and tablet disintegration time, respectively, using Design Expert 9. In conclusion, combinations of directly compressible excipients and disintegrant were effectively optimized for the formulation of diclofenac tablets.