Plant Factories using exclusively artificial lighting (PFAL) provide a short and secure food chain, and optimize the use of resources such as soil, water, and nutrients. They can also exploit the availability of abandoned industrial buildings in urban settings, once suitably adapted. However, PFALs have considerable energy requirements due to the need for artificial lighting and environmental conditioning all year round. In this case study, we considered a disused reinforced concrete building in a metropolitan area in Southern Italy, where we hypothesize the installation of a PFAL for fresh-cut vegetable production on multi-level shelves using soilless cultivation. The objective is minimizing the PFAL’s energy requirements through various systems of thermal insulation of the building external envelope, with a thermal transmittance ranging in 0.10–2.20 W m−2 K−1, and with reference to various cultivation areas, from 1102 to 8820 m2. The study was conducted through thermo-energy simulations, using Design Builder-Energy Plus software. The results indicate that at low levels of cultivation area thermal insulation allows an energy reduction of 10.6%. Furthermore, the ratio of energy demand to annual vegetable productivity decreases, as the cultivation area increases, by 14.1% and 18.3% for a thermal transmittance of 0.10 W m−2 K−1 and of 2.20 W m−2 K−1, respectively.