Using high shear mixers (HSMs) as the vessel to intensify chemical processes requires knowledge of the residence time distribution (RTD) characteristic. Considering the numerous structural characteristics of HSMs, a series of pilot-scale HSMs was developed to investigate the RTD characteristics through pulse tracing and deconvolution. A number of structural parameters were included here, including tooth height, tooth thickness, and the number of rotor-stator tooth rows, slots, and stages. Meanwhile, by using CFD simulations with the large-eddy simulation model coupled with the sliding mesh method, the flow rate, power consumption, and energy dissipation rate distribution, as well as RTD of HSM were examined. It is illustrated that adding a distributor or increasing rotor speed improves the local energy dissipation, reducing short-circuits and dead zone. The RTD curves become smoother and closer to plug flow with increasing stator-rotor stages. Typical first/second-order reactions are favored by higher or thicker rotor-stator teeth, and HSM is better suited when kR1 > 1 s−1 or kR2cA0 > 5 s−1. Furthermore, the correlations of E(t), tR, σθ2, Potot, and qave, 1+ were obtained, which would provide useful guidance on the scale-up design and optimization of HSMs.