Process cooling for food production is an energy-intensive industry with complex interactions and restrictions that complicate the ability to utilize energy-flexibility due to unforeseen consequences in production. Therefore, methods for assessing the potential flexibility in individual facilities to enable the active participation of process-cooling facilities in the electricity system are essential, but not yet well discussed in the literature. Therefore, this paper introduces an assessment method based on multi-method simulation and multi-objective optimization for investigating energy flexibility in process cooling, with a case study of a Danish process-cooling facility for canned-meat food production. Multi-method simulation is used in this paper: multi-agent-based simulation to investigate individual entities within the process-cooling system and the system’s behavior; discrete-event simulation to explore the entire process-cooling flow; and system dynamics to capture the thermophysical properties of the refrigeration unit and states of the refrigerated environment. A simulation library is developed, and is able to represent a generic production-flow of the canned-food process cooling. A data-driven symbolic-regression approach determines the complex logic of individual agents. Using a binary tuple-matrix for refrigeration-schedule optimization, the refrigeration-cycle operation is determined, based on weather forecasts, electricity price, and electricity CO2 emissions without violating individual room-temperature limits. The simulation results of one-week’s production in October 2020 show that 32% of energy costs can be saved and 822 kg of CO2 emissions can be reduced. The results thereby show the energy-flexibility potential in the process-cooling facilities, with the benefit of overall production cost and CO2 emissions reduction; at the same time, the production quality and throughput are not influenced.