In the manufacturing industry, flexible manufacturing systems (FMS) are gaining importance in meeting the demand for product customization while maintaining high manufacturing efficiency. The digitization of physical manufacturing additionally expands the relevance of industrial communication networks, resulting in complex interactions of material, energy and information flows that pose challenges for the manufacturing system design. Existing decision support frameworks for the design of FMS mainly incorporate the evaluation of the material flow. A holistic view of FMS requires the consideration of the interdependencies of the material, energy and information flow. Particularly, the performance of the material flow of a manufacturing system increasingly depends on the information flow of the connected communication network. Against this background, the paper presents a simulation-based framework that enables the integrated quantitative evaluation of material, energy and information flows in FMS as decision support in manufacturing system design. The framework contains a modular reference model of a generic FMS and its communication network to reduce modeling efforts. It further provides a procedure and an evaluation model that enable a multi-criteria comparison of different FMS configurations. The functionality and benefits of the developed framework are examined with the help of an exemplary case study involving an FMS for producing and recycling polymer parts.