This work aims at simulating a retort sterilization process of flexible packaging, performed in autoclave. ANSYS CFD© software has been used in this study to simulate the heat transfer inside the retort chamber. Flexible packaging filled with a pumpkin soup has been modelled. Three-dimensional (3D) geometrical configuration of the equipment has been designed and then simulated to evaluate the sterilization level achieved by each packaging inside the retort chamber. In particular, the internal temperature of the product situated in the cold spot of the chamber has been monitored during 5 min of the process (after reaching 85°C inside the product) in order to monitor the time/temperature trend. Experimental tests have been finally performed to validate the simulation model of heat exchange. The sterilization process takes place in a retort chamber by means of “overheated water sprayed” at 403 K and a pressure of 5 atm. Results show a good agreement between the simulated results and the real retort process and confirm the potential value of the simulation model to evaluate the process performance.