Abstract: The efficient and compact microbubble generation technology and particle size control technology are the premise and foundation of large-scale industrial application of microbubble technology. The foaming characteristics of gas-liquid two-phase mixing in two-stage Venturi series bubble generator were studied employing CFD numerical simulation and experimental test, the key structural parameters were optimized, and the interactions were analyzed by Response Surface Method. The results showed that the diameter of the throat in the second stage had the greatest influence on the bubble particle size of the two-stage Venturi series bubble generator, followed by the diameter of the throat in the first stage and the second stage expansion angle, while the expansion angle in the first stage had the least influence. Under the same working conditions, the median particle size of bubbles generated by single-stage Venturi bubble generator was 543.64 μm, and the proportion of fine bubbles with particle size less than 100 μm was 8.6%. The median particle size of bubbles generated by two-stage Venturi series bubble generator was 515.99 μm, and the proportion of fine bubbles increased to 12.1%. Thus by controlling the flow rate and changing the number of Venturis in series, the bubble particle size could be adjusted from millimeter level to micron level.