A nanobubble generator with honeycomb structures producing a large amount of water including large nanobubble density in a short time is described. The nanobubble-generating performance is investigated for large and small apparatus having different honeycomb cell dimensions by applying computational fluid dynamics (CFD) coupled with a population balance model (PBM). The CFD simulation shows that a significant pressure drop and shear stress occur in the bubbly flow in the honeycomb cell. The numerical model is based on the Eulerian multiphase model and the PBM is used to calculate the bubble size distribution. The obtained CFD-PBM results are compared with the experimental results for large and small apparatus. Bubble size distributions in the honeycomb structure under different inlet absolute pressure can be predicted by the PBM. The maximum shear stress is determined as the main controlling factor for nanobubble generation.