This paper deals with the selection of refrigerants and simulation of Auto Refrigeration Cascade (ARC) system, which is generally used for low temperature applications in the range of -40 to -150°C that operates with zeotropic mixture, containing two or more refrigerants with different boiling points. The selection of refrigerants depends on the working pressure and temperature range of operation. In order to have effective phase separation, the minimum difference in the boiling points should be in the order of 40 to 80°C. Moreover, the ODP and GWP values are considered in the process of selection. Initially 52 combinations are selected and then reduced to 20, based on environmental friendliness. A further elimination process is undertaken based on suitable condensing and evaporating temperatures for effective heat transfer in cascade condenser and three refrigerant mixtures, R23/R290, R23/R600 and R125/R600, are selected. Due to some mismatch of physical properties like triple point of low boiling component in CO2 and HFC 134a mixture at low temperature applications, it is not considered in the refrigerant selection. The mass fractions of above refrigerant pairs are calculated by applying energy balance in the cascade condenser. The above mass fraction and unit refrigeration capacity is used for the simulation of the system. Exergy analysis is used to select the efficient refrigerant pair, which gives overall minimum exergy loss by simulating the system. The exergy loss in different components in the ARC system with R23/R290 mixture (Compressor: 20 and 14.28%, Condenser: 35.01 and 30%, Separator: 16.12 and 10.65%, Cascade condenser: 8.7 and 16%, Expansion valve I: 9.04 and 16%, Expansion valve II: 7 and 15%, Evaporator: 7.3 and 7.3%) is less in comparison with R125/R600 and R23/R600 mixtures and thus an R23/R290 mixture is recommended for this specific application.