Gas/particle interaction plays an important role in modern spray dryers and may have influences on wall deposition, agglomeration, powder degradation, etc. In the present study, the three-dimensional (3-D) transient multiphase flow in an industrial-scale spray dryer has been investigated using the CFD package FLUENT. The Eulerian-Lagrangian approach and two-way coupling method were used in the simulations. The reaction engineering approach (REA model) for milk particles has been implemented. Some new characteristics of the gas flow pattern and the particle behavior (e.g., temperature-time profiles) were identified from the numerical results; for example, the milk particles flow in such a way that makes the central jet oscillation more nonlinear. The discrete phase enhances the turbulence near the air/droplet inlet but damps it downstream. The transient turbulent flow causes significant uncertainties in the particle tracking, which presented some challenges in simulations. The study has highlighted the importance in performing 3-D transient simulations in order to understand the industrial-scale dryers.