The aim of this paper is to propose a simulation study to assess the advantages deriving from associating plant layout (PL) modifications and the introduction of some key technologies of the fourth industrial revolution in a production and assembling environment of bus transportation vehicles. The software Simul8® was used to design and realize a simulation model relying on the information and data coming from a real working environment. Six experiments were carried out to test the model, mixing different PL configurations and technologies that were assumed to improve the working times of the different production and assembling phases. The results demonstrate the feasibility of the simulation model and its good accuracy in reproducing the behavior of the working environment. The simulation approach allowed to identify feasible solutions for reducing the lead times and minimizing the issues related to the bottlenecks that characterize the actual working environment for each type of bus produced.