In this paper an integrated simulation and optimization approach for real-time operation management of on-site energy systems within manufacturing facilities is proposed and evaluated. Expected outcomes of on-site energy systems are highly dependent not only on system sizing but are also affected by system utilisation. The latter is dependent on the choice of operational management strategy for integrated components. Although fixed operational strategies can guarantee reliable performance and enhance the outcomes of individual components, system effectiveness can drop severely at the utilisation stage in the presence of multiple energy supply options and operating environment dynamics. There is, therefore, a need for autonomous operation management systems that can compensate for the existing shortcomings of fixed operational strategies. Real-time optimization of controllable options has shown potential for continuous and optimal decision-making. However the lack of a reliable, optimal and practical solution has been identified.In this paper we present, an exemplar model with real-time application, which not only covers the mechanical integrity of the components, but also address the specific requirements for real-time application. In addition, a simulation-based methodology for real-time optimization is described. The proposed autonomous management scheme would continuously guarantee system reliability, unit commitment, and optimal operational objectives. Finally the proposed approach is simulated and evaluated for the case study of an existing manufacturing plant. The results illustrate the potential for improvement as well as applicability compared to existing operational management approaches.