Engineered ZnO quantum dots (E-QDs) are sought-after nanostructures in healthcare and optoelectronic industries, necessitating a paradigm shift toward high-throughput continuous flow platforms, the crux to whose successful design and performance lies in comprehending the nucleation-growth kinetics, defect engineering, and reaction dynamics. This work investigates the synergistic interplay of enhanced hydrodynamics and heat–mass transfer in the helical coil reactor, fostering rapid nucleation-growth-driven E-QDs fabrication. We integrated computational fluid dynamic modeling, and comprehensive experimentation for producing E-QDs with record-high photoluminescence quantum yield (PLQY) (∼89% in the yellow-green spectrum) by carefully creating oxygen vacancies via a novel reproducible protocol. Dean vortices formed due to the helical geometry facilitated ultrafast mixing and accelerated reaction kinetics, yielding colloidally stable E-QDs in gram-scales [ζ = −39.7 mV, polydispersity index (PDI) ∼0.22] with a narrow particle size distribution (average particle size ∼4.5 nm). Contrastingly, the conventional batch route produced less stable E-QDs with ζ value of −15.3 mV, PDI ∼0.41, and diminished PLQY (∼40%) because of inadequate process control, batch-to-batch variability due to poor mixing, and heat transfer. The simple, economical, in-house-fabricated flow reactor manifested ∼90% increment in yield and reduced product cost. Thus, this research demonstrated the benefits of simulation-driven process engineering and reactor design in catalyzing QDs-based innovations.