Design of Experiments (DoE) is acknowledged as a mathematical/statistical technique exploited in pharmaceutical research and development to swiftly optimize drug delivery systems’ effectiveness on the basis of known input factors. The first step is a screening experimental design test plan that includes every known variable suspected of having a significant effect on the drug delivery system’s pharmacokinetic or pharmacodynamic accomplishments. Reducing the number of test factors or input variables to a reasonable quantity is the main goal of the experiment when there are many of them. Another test plan or experimental design is typically used to give a boost to the drug delivery system’s performance for predetermined therapeutic results. The use of DoE software and methodology allowed the pharmaceutical researchers to quantify the dominance of several prominent factors on the predefined attributes and performance of medication delivery system under examination. By using DoE, formulation performance might be quickly optimized across a wide range of relevant factors to achieve the intended therapeutic effects. The DoE will be thoroughly followed up on in this chapter, with the goal of optimizing pharmaceutical formulations while minimizing the number of actual experimental runs.