One of the possible ways to face the challenge of reducing the environmental impact of aviation, without limiting the growth of air transport, is the introduction of more efficient, radically different aircraft architectures. Among these, the box-wing one represents a promising solution, at least in the case of its application to short-to-medium haul aircraft, which, according to the achievement of the H2020 project "PARSIFAL", would bring to a 20% reduction in terms of emitted CO2 per passengerkilometre. The present paper faces the problem of estimating the structural mass of such a disruptive configuration in the early stages of the design, underlining the limitations in this capability of the approaches available by literature and proposing a DoE-based approach to define surrogate models suitable for such purpose. A test case from the project "PARSIFAL" is used for the first conception of the approach, starting from the Finite Element Model parametrization, then followed by the construction of a database of FEM results, hence introducing the regression models and implementing them in an optimization framework. Results achieved are investigated in order to