This work presents a detailed thermodynamic analysis of a triple cascade vapor refrigeration system (TCRS) utilizing hydrocarbon refrigerants for ultra-low temperature application. Different hydrocarbon refrigerants pairs are used in different circuits (High temperature circuit HTC, Mid temperature circuit MTC, and Low temperature circuit LTC) to obtain the most suitable refrigerant combination by mathematical modeling of the system. The design and operating parameters considered in this study include (1) evaporator temperature (2) LTC condensation temperature (3) MTC condensation temperature. A thermodynamic analysis consisting of energy and exergy analysis were employed in terms of operating conditions to obtain COP, total compressor work, exergy efficiency, total exergy destruction, mass flow rate and discharge temperatures of compressors. Furthermore, an analysis on component exergy destruction was conducted to show the possibilities of improvement of TCRS utilizing the hydrocarbon refrigerants. The results suggest that at different evaporator temperatures different hydrocarbon refrigerants on TCRS give higher COP and exergy efficiency. The highest COP and exergy efficiency at −100 °C evaporator temperature was calculated to be 0.5931 and 54.446 %, respectively. This study also suggests that hydrocarbon refrigerants can be used in ultra-low temperature applications without compromising the thermodynamic performance of the refrigeration system.