Despite the great potential of design of experiments (DoE) for efficiency and plannability in academic research, it remains a method predominantly used in industrial processes. From our perspective though, DoE additionally provides greater information gain than conventional experimentation approaches, even for more complex systems such as chemical reactions. Hence, this work presents a comprehensive DoE investigation on thermally initiated reversible addition–fragmentation chain transfer (RAFT) polymerization of methacrylamide (MAAm). To facilitate the adaptation of DoE for virtually every other polymerization, this work provides a step-by-step application guide emphasizing the biggest challenges along the way. Optimization of the RAFT system was achieved via response surface methodology utilizing a face-centered central composite design (FC-CCD). Highly accurate prediction models for the responses of monomer conversion, theoretical and apparent number averaged molecular weights, and dispersity are presented. The obtained equations not only facilitate thorough understanding of the observed system but also allow selection of synthetic targets for each individual response by prediction of the respective optimal factor settings. This work successfully demonstrates the great capability of DoE in academic research and aims to encourage fellow scientists to incorporate the technique into their repertoire of experimental strategies.