In the present paper, a novel Single-Minute Exchange of Die (SMED) set-up reduction approach, fully integrated with a 5-Whys Analysis, is presented. It permits to highlight not-optimized conditions from the changeover perspective, with the aim of reducing the effort and the cost of the SMED activity. Indeed, all set-up losses are investigated in a structural manner to identify their root causes and all the possible interactions, thus suggesting better—in terms of efficiency—interventions. In this way, the analyst is supported and facilitated during the definition of the actions required to reduce the set-up times. In particular, the implementation of the ‘why-why analysis’ is supported and integrated with (i) a general schematization of the generic workstation and (ii) an operational worksheet that leads the analyst through the investigation of the machine and its set-up process. The proposed approach is applied to a real industrial context, and the outcomes of such application are presented in the provided case study.