BACKGROUND: The universal availability of smartphones has created new opportunities for innovative telemedicine applications in health care. The COVID-19 pandemic has heightened the demand for contactless health care services, making SARS-CoV-2 polymerase chain reaction (PCR) testing a crucial component of pandemic containment. OBJECTIVE: This feasibility study aimed to examine a comprehensive telemedicine approach for SARS-CoV-2 testing, focusing on the practicality, user satisfaction, and economic implications of self-sampling guided by a telemedicine platform. METHODS: The study process involved shipping self-sampling kits, providing instructions for at-home sample collection, processing biomaterials (swabs and capillary blood), communicating test results, and providing interoperable data for clinical routine and research through a medical mobile app. A total of 100 individuals were randomly assigned to either the conventional health care professional (HCP)-performed SARS-CoV-2 testing group (conventional testing group, CG) or the telemedicine-guided SARS-CoV-2 self-sampling approach (telemedicine group, TG). Feasibility of the TG approach, user satisfaction, user-centered outcomes, and economic aspects were assessed and compared between the groups. RESULTS: In the TG group, 47 out of 49 (95%) individuals received a self-sampling kit via mail, and 37out of 49 (76%) individuals successfully returned at least one sample for diagnostics. SARS-CoV-2 PCR tests were conducted in 95% (35/37) of TG cases compared with 88% (44/50) in the CG. Users in the TG reported high satisfaction levels with ease of use (5.2/7), interface satisfaction (5.2/7), and usefulness (4.3/7). A microcosting model indicated a slightly higher cost for the TG approach than the CG approach. The TG demonstrated the potential to facilitate interoperable data transmission by providing anonymized, standardized datasets for extraction using Health Level 7-Fast Healthcare Interoperability Resources. This supports the national COVID-19 Data Exchange Platform and facilitates epidemiological evaluation based on the German COVID Consensus dataset. CONCLUSIONS: These preliminary findings suggest that a telemedicine-based approach to SARS-CoV-2 testing is feasible and could be integrated into existing hospital data infrastructures. This model has the potential for broader application in medical care, offering a scalable solution that could improve user satisfaction and treatment quality in the future.