Telemedicine has progressively evolved from a complementary digital service into a structural component of contemporary care models. This transition has transformed telemedicine into a complex intervention whose effectiveness depends not only on technological performance, but also on the dynamic interactions among organizational processes, professional practices, patient engagement, infrastructural conditions, and governance arrangements. Although established multidimensional frameworks, such as Health Technology Assessment (HTA), provide robust methodological foundations for evaluating health technologies, their application at the regional ecosystem level still presents relevant challenges. In particular, traditional assessment approaches often struggle to capture the adaptive nature, contextual variability, stakeholder interdependencies, and systemic trade-offs that characterize telemedicine as a socio-technical system. Against this background, a persistent gap remains between the theoretical recognition of telemedicine complexity and the availability of operational tools capable of monitoring such complexity in an integrated and decision-oriented manner. This study addresses this gap by proposing the Telemedicine Ecosystem Monitoring and Evaluation Framework (TEMEF), an HTA-informed and context-sensitive model designed to support the evaluation of telemedicine systems in regional healthcare contexts. Rather than replacing existing evaluative approaches, TEMEF aims to complement them by translating multidimensional assessment principles into a structured, multi-stakeholder monitoring architecture. Using a Proof of Concept (PoC) methodology, the paper describes the transition from conceptual design to the development of a survey-based evaluation system tailored to four key stakeholder groups: patients and caregivers, physicians, healthcare managers, and technology providers. The framework integrates five main evaluative domains—clinical, organizational, technological, experiential, and economic—allowing system performance to be examined both at an aggregate level and through stakeholder-specific perspectives. To assess the internal coherence of the scoring logic and the interpretability of the analytical outputs, AI-generated synthetic stakeholder profiles were used to conduct a preliminary stress-test of the framework and its analytical dashboard interface. This procedure enabled the exploration of plausible configurations of stakeholder alignment and misalignment, highlighting how apparently positive aggregate performance may conceal critical tensions across domains or actor groups. The resulting model provides policy makers and healthcare decision-makers with an operational framework for interpreting telemedicine not as an isolated technological solution, but as a regional healthcare ecosystem. TEMEF supports evidence-informed governance by making visible systemic trade-offs, implementation bottlenecks, and areas requiring targeted improvement, thereby contributing to the sustainable integration of telemedicine into evolving care delivery models.