Abstract This paper presents a novel dynamic simulation model for the analysis of a hybrid turboexpander system coupled with innovative high-vacuum solar thermal collectors. The model is developed in MatLab and it is able to dynamically calculate the energy, exergy, environmental, and economic performances of the investigated system, by taking into account the hourly fluctuation of thermodynamic and economic parameters (e.g. electricity cost, natural gas temperature, and flow rates, etc.). In addition, a computer-based Design of Experiment (DoE) approach was implemented for achieving the optimal design of the proposed system. A suitable case study is presented in order to show the capabilities of the developed simulation tool. Conventional and non-conventional decompression systems located in the weather zone of Messina (South-Italy) are investigated with the aim of assessing the optimal system configuration. By means of the computer-based DoE analysis, the optimal values of several design parameters (such as the number of solar thermal collectors, the volume of the hot water storage tank, and the size of the water loop pump) are calculated. Numerical results show significant primary energy savings (1.36 TWh/year) and avoided carbon dioxide emissions (348 tCO2/year). From the economic point of view, a feasible simple pay-back period of 4.51 years is achieved. The destroyed exergy of the system components are calculated, obtaining the highest value for the turbo-expander, equal to 12.0 TWh/year.