The introduction of disruptive innovations in the transport aviation sector is becoming increasingly necessary. This is because there are many very demanding challenges that the transport aviation system will have to face in the years ahead. In particular, the reduction in pollutant emissions from air transport, and its impact on climate change, clearly must be addressed; moreover, sustainable solutions must be found to meet the constantly increasing demand for air traffic, and to reduce the problem of airport saturation at the same time. These three objectives seem to be in strong contrast with each other; in this paper, the introduction of a disruptive airframe configuration, called PrandtlPlane and based on a box-wing lifting system, is proposed as a solution to face these three challenges. This configuration is a more aerodynamically efficient alternative candidate to conventional aircraft, introducing benefits in terms of fuel consumption and providing the possibility to increase the payload without enlarging the overall aircraft wingspan. The development and analysis of this configuration, applied to a short-to-medium range transport aircraft, is carried out through a multi-fidelity physics-based approach. In particular, following an extensive design activity, the aerodynamic performance in different operating conditions is investigated in detail, the structural behaviour of the lifting system is assessed, and the operating missions of the aircraft are simulated. The same analysis methodologies are used to evaluate the performance of a benchmark aircraft with conventional architecture, with the aim of making direct comparisons with the box-wing aircraft and quantifying the performance differences between the two configurations. Namely, the CeRAS CSR-01, an open-access virtual representation of an A320-like aircraft, is selected as the conventional benchmark. Following such a comparative approach, the paper provides an assessment of the potential benefits of box-wing aircraft in terms of fuel consumption reduction and increase in payload capability. In particular, an increase in payload capability of 66% and a reduction in block fuel per pax km up to 22% is achieved for the PrandtlPlane with respect to the conventional benchmark, while maintaining the same maximum wingspan.