Flow chemistry coupled with microreactor technology represents a contemporary advancement in the chemical industry. This approach integrates chemical synthesis, organic chemistry, and green chemistry, offering enhanced safety for hazardous chemical operations. In the present study, the continuous flow synthesis and separation of diazoacetate ethyl ester (EDA) in a microchannel reactor were investigated using glycine ethyl ester hydrochloride (GEE), sodium nitrite, and acetic acid as starting materials, with 1,2-dichloroethane utilized as an extractant. Response surface analysis (RSM) was adopted to determine appropriate test design factors and levels using singlefactor experiments as a basis, and a model was constructed by means of the Box−Behnken Design (BBD) central combination principle. The effects of reaction temperature (5−15 °C), GEE to acetic acid molar ratio (1: 2.8−3.2), residence time (90−150 s), and GEE to sodium nitrite molar ratio (1: 1.0−1.2) were investigated, examining the interactions among these factors to determine their combined effects on the yield of the diazotization process. The optimal process conditions for synthesizing ethyl diazoacetate in a microchannel reactor were determined: n(GEE):n(sodium nitrite):n(acetic acid) = 1:1.154:3.069, reaction temperature of 9.82 °C, and residence time of 135.18 s. The yield of GEE diazonium salt under such conditions was predicted to be 95.02%. The results reveal that the residence time significantly affected the yield of the product. Additionally, a three-dimensional computational fluid dynamics model was developed for the microchannel reactor to predict flow patterns and micromixing efficiency during the iodate− iodide reaction. As demonstrated, velocity, path lines, and concentration distributions inside the reactor could be visualized by examining the effects of Re, volumetric flow ratio (R), and initial H + concentration on micromixing efficiency (representative of the segregation index X S ). X S decreased with increasing Re or decreasing R or initial H + concentrations. The control system for the integrated continuous flow preparation of EDA, which integrates continuous production, extraction, and separation, provides a novel approach for industrial production.