A unique method of coupling computational fluid dynamics (CFD) to model predictive control (MPC) for controlling melt temperature in plastic injection molding is presented. The methodology is based on using CFD to generate, via open-loop testing, a temperature and input dependent system model for multi-variable control of a three-heater barrel on an injection molding machine. Results clearly show the benefit of temperature and input dependent system models for MPC control, and that CFD can be used to dramatically reduce the time associated with open-loop testing through physical experiments.