The Italian existing building stock is mostly aged and characterized by low-performance levels in terms of energy efficiency and seismic safety. The development of intervention solutions that fulfil both targets is therefore of strong interest, as proven by a series of fiscal incentives recently approved, in Italy, to encourage the implementation of both energy and seismic intervention. Nevertheless, energy and seismic retrofitting techniques often present specific features that make it difficult to pursue both objectives. In this framework, an innovative solution is proposed, focused on the enhancement of unreinforced masonry (URM) buildings using expanded-clay blocks infill walls. Expanded-clay block walls technique has proven to provide excellent energy performance and ensure high seismic safety in new buildings. The feasibility and the efficiency of this technique as a retrofit solution have been analysed through a 3D model of a case study building in its current state and for the retrofitted configuration. Dynamic thermal simulations have been carried out to evaluate the hygrothermal performance, showing a general decrease in the overall thermal transmittance and an improvement in the indoor thermal comfort for the retrofitted configuration. The seismic behavior of the coupled system has been assessed by means of linear dynamic analysis. Results showed the increasing capacity of the building in the retrofitted configuration towards horizontal actions, confirming the positive effect provided by the infill walls. In sum, even if the presented combined system has not yet been fully investigated, due to the strong innovation of the solution, preliminary results have proven successful.