This work presents the optimization of a two stage-cascade refrigeration system (TS-CRS), based on exergetic, economic, environmental, and sensitive analysis (3ES). R134a and R744 are considered as the refrigerants of high and low temperature circuits, respectively. Two single-optimization strategies including exergetic and economic optimizations and a multi-objective optimization are applied on the problem. In the first step, a comprehensive performance evaluation of different effective parameters, based on the genetic algorithm, used to indicate the optimum operative conditions in single objective strategies. In the next step, a multi-objective optimization is performed with considering a decision-making strategy based on the Pareto frontier using TOPSIS method. The higher exergetic efficiency and lower cost found in the exergetic and economic single-optimization, respectively. The multi-objective optimization results demonstrate that, the total system cost and the exergetic efficiency increase 28.6% and 99.5%, respectively, compared to the base design, and 46.6% higher energy can be saved in the compressors.