The term “cyber-physical system (CPS)” refers to a computing system that integrates physical processes and computational devices via a network. There are many physical and computational devices in a CPS, which can function automatically through inter-device interactions. Because a CPS is usually used for large-scale complex systems, to ensure reliable CPS operation, its design and execution should be verified through simulations. For CPS simulation, a communication protocol should be established for data transmission between physical systems and the corresponding simulation models during the simulation, including control algorithms for regulating differences between the two systems. First, because physical systems and simulation models are advanced in real time and logical time, respectively, time regulation methods should be included in the control algorithm. Second, to simulate various types of physical systems, a flexible simulation environment, independent of the operating environment such as the type of communication middleware, is required. In this paper, we propose a communication protocol for data transmission between physical systems and simulation models via a middle layer that contains the policies for handling the two different clocks of each system: virtual and real. The proposed communication protocol can be used not only for communication between the two systems but also for overcoming the problems caused by the differences in their operating environments. The contribution of this work is in that it defines a communication protocol and proposes methods for controlling different types of systems.