“Giant” core/thick-shell quantum dot (QD) nanostructures are of interest due to their unusual optical properties and importance as components of more advanced heterostructures tailored to achieve increasingly complex optical functions. However, reliable one-step seeded growth of these structures poses a significant challenge: one must balance multiple competing reaction processes to find the growth regime that realizes spherical shells of both the target size and high crystalline quality. Adjusting synthesis conditions in thicker-shelled reactions is further complicated by multiple nonorthogonal variables that impact the reaction mechanism. These variables include the reaction volume, reaction concentration, and oleic acid (ligand) concentration. Here, we investigate the seeded growth of core/thick-shell CdTe/CdS QDs by adapting a “flash” shelling method. We systematically vary three key reaction parameters (particle concentration, oleic acid:Cd ratio, and Cd–S:CdTe core ratio) over 30+ different thick-shelling reactions to elucidate the separate and intersecting impacts of these parameters on shell growth. Our analysis of the resulting particle quality reveals that the particle concentration of the reaction plays a critical role in the shell growth mechanism. We find the impact of oleic acid to be dependent on the particle concentration for a given shell thickness. We also find that the optimal conditions shift when targeting increasingly thick shells. The results demonstrate the importance of testing and controlling for synthesis variables across a multidimensional parameter space. We develop and present general experimental design criteria to help guide efficient development of new seeded growth reactions that enable reliable synthesis of thick-shelled nanostructures.