The growing integration of intermittent renewable energy sources (RESs) and the increasing trend of shutting down fossil-fuel-based power plants has brought about the need for additional flexibility in energy systems. This flexibility can be provided in various forms, including controllable generation and consumption, storage, conversions, and exchanges with interconnected systems. In this context, an increasing focus is placed on the development of smart energy systems (SESs) that combine different types of distributed energy resources (DERs), information and communication technologies (ICTs), demand side management (DSM), and energy conversion technologies. The utilization of SESs can lead to multiple benefits for the stakeholders involved; therefore, the assessment of their performance is a primary concern. Due to their multidisciplinary nature, there are no known or universally accepted standards for assessing the performance of SESs. Previous efforts only define key performance indicators (KPIs) for individual homogeneous subsystems, focusing on a specific SES type and application area. This paper focuses on the development of a novel comprehensive KPI framework that can be applied to any type of SES, regardless of the application area. The proposed framework consists of four layers that specify the application area, the main SES requirements, and the involved stakeholders’ objectives. Next, the KPIs are identified for each of the stakeholders’ objectives. The proposed KPI framework is applied to the use case of a European research project with different application areas, to demonstrate its features. Finally, a repository of KPIs is identified for each use case with respect to the aforementioned SES requirements.