With the growing global energy consumption, on the first hand, and the need to produce low temperatures on the second hand, therefore the technological challenges consist in minimizing greenhouse gas emissions by reducing the energy consumption. In fact, in refrigeration, this consists of the use of environmentally friendly refrigerants (GWP < 150) with the optimization of cold production processes. In this context, several optimization methods have been tested, and the objective of this work to seek the most reliable method to optimize a three-stage cascade vapor compression refrigeration system. Regarding refrigerants, hydrocarbons can be a solution, the R50/R1150/R290 and R50/R1150/R1270 groups are selected and used here to produce temperatures ranging from −160 °C to −120 °C. After comparing seven (7) nature-inspired optimization methods, the JSOA bio-inspired optimization method is applied. Energetic, exergetic and environmental analyzes are also applied to determine the optimal operating point that allows both the minimization of energy consumption and TEWI (Total Equivalent Warming Impact). A pragmatic comparison between the two considered groups provides insights into the choice of high-temperature sub-cycle fluid, and it is found that R290 shows better results compared to R1270.