The microfluidic technology for function microsphere synthesis has high control precision. However, the throughput is too low for industrial scale-up applications. Current scale-up design focuses on a multi-channel in 2D, in which the distribution uniformity parameter δ increases linearly, resulting in the deterioration of the flow distribution performance. The 3D modular scale-up strategy could greatly alleviate this problem, but no design principles have been developed yet. For the first time, this paper establishes the microfluidic 3D scale-up design criteria. Based on the modular design concept, the design method of 2D and 3D throughput scale-up parameters N and M, distribution uniformity parameters δ and β, and microchannel design parameter KR were proposed. The equivalent resistance coefficient was defined, and the influence of different parameters on a 2D array and 3D stack was analyzed. Furthermore, the error correction method was studied. It was found that the two-stage scale-up process contradicted each other. A good scale-up performance of one stage led to the limitation of another stage. Increasing the resistance of each channel Ru could both increase the two-stage scale-up performance, which was an important factor. A single-module scale-up system with 8 channels in a single array and 10 arrays in a vertical stack, which had 80 channels in total, was designed and fabricated based on the proposed design criteria for generating Chitosan/TiO2 composite microspheres. The average particle size was 539.65 µm and CV value was about 3.59%. The throughput was 480 ml h−1, which effectively increased the throughput scale and the product quality.