Integrated operation of distribution grids for multiple energy carriers promises hitherto unused synergies in terms of efficient generation, storage, and consumption. A major obstacle to the investment in such systems is their increased complexity, as conventional tools and methods were not designed to capture all relevant technical and economic aspects of hybrid grids. To address this obstacle, this work proposes a methodology to systematically assess multi-carrier energy grids under a holistic scope. By adopting a simulation-based approach that relies on detailed technical and economic models, an efficient and precise evaluation of both short-term (operational) and long-term (strategic) aspects is supported. The methodology enables the assessment of system configurations, control strategies, business models, and regulatory conditions in one coherent approach. As a proof-of-concept, the new methodology is applied to a real-world use case of a hybrid thermal-electrical distribution grid in a central European city. The results are comprehensively discussed to showcase how the various aspects of hybrid energy systems are addressed. The outcomes also demonstrate how this methodology aids the involved stakeholders in understanding the associated risks and potentials, paving the way for early adopters to realize multi-carrier energy distribution grids. •A holistic methodology to study multi-carrier energy systems is presented.•Operational technical and strategic economic perspectives are considered.•Established tools for different domains are coupled in a co-simulation framework.•Multiple market participants and opposing objectives are taken into account.•The methodology is demonstrated by a comprehensive study in a central European city.