The computational fluid dynamics-population balance model (CFD-PBM) has been presented and used to evaluate the bubble behavior in a large-scale high pressure bubble column with an inner diameter of 300 mm and a height of 6600 mm. In the heterogeneous flow regime, bubbles can be divided into “large bubbles” and “small bubbles” by a critical bubble diameter dc. In this study, large and small bubbles were classified according to different slopes in the experiment only by the method of dynamic gas disengagement, the critical bubble diameter was determined to be 7 mm by the experimental results and the simulation values. In addition, the effects of superficial gas velocity, operating pressure, surface tension and viscosity on gas holdup of large and small bubbles in gas−liquid two-phase flow were investigated using a CFD-PBM coupling model. The results show that the gas holdup of small and large bubbles increases rapidly with the increase of superficial gas velocity. With the increase of pressure, the gas holdup of small bubbles increases significantly, and the gas holdup of large bubbles increase slightly. Under the same superficial gas velocity, the gas holdup of large bubbles increases with the decrease of viscosity and the decrease of surface tension, but the gas holdup of small bubbles increases significantly. The simulated values of the coupled model have a good agreement with the experimental values, which can be applied to the parameter estimation of the high pressure bubble column system.