Distillation is a key separation technology for the chemical and petrochemical industries. However, high energy consumption is drastically associated with distillations. Achievement of 0.99 product purity in a mixture separation process requires more than one distillation column. This leads to many possible configurations of distillation columns for separating a multicomponent mixture. The number of possible separation sequences increases dramatically with the number of product components. Exergy analysis has appeared as a beneficial method to quantify the sources of energy consumption in the process and optimize the most efficient alternative for a large number of multicomponent mixtures separation alternatives. The main objective of the current work is to obtain an optimal distillation sequence among different sequences for ternary, quaternary and quinary systems by applying exergy analysis to meet the desirable pure products with the minimum energy consumption. A separation of benzene, toluene and xylene was applied in the ternary system. A distillation of ethane, propane, i-butane and n-butane was carried on the quaternary system. In the quinary system, there was a separation of propane, i-butane, n-butane, i-pentane and n-pentane in different sequences. The use of exergy as an analysis tool has grown to a point where it can prove the possibility of designing more efficient systems by minimizing the deficiencies in existing systems and identifying whether a system is applicable to achieve sustainable development. To accomplish the analysis of the ternary, quaternary and quinary systems, the distillation separations of the mixtures into pure components were modelled using Aspen Hysys. The inputs were constant for all the sequences of the same type system. Data related to mass and energy obtained from Aspen Hysys model has been extracted and transferred to excel to calculate streams' exergy and thermodynamic efficiency of the distillations. Irreversibility sources were found in the mass transfer of the phases, heat transfer in reboilers, heat exchange in condensers, heat transfer caused by flows inside the column and column external surface heat losses. The results illustrated that the direct method at which benzene, toluene and xylene were separated in sequence was the optimum configuration in the ternary system. The direct method can save around 90% of the energy used in the indirect method. In the quaternary system, separating nbutane first followed by ethane separation then propane and i-butane separately consumed small amount of energy and with low amount of entropy and became the optimum alternative. It can save energy from 6 to 21%. In the quinary mixture, it was concluded that separating propane, ibutane, n-pentane, n-butane and i-pentane in sequence is exergetically beneficial and optimal with good product purity. Energy savings of the quinary system optimal sequence was ranged between vi 21% to 70%. Temperature change between summer and winter had an impact on exergy of the ternary, quaternary and quinary systems. As environment/system temperature difference increased, the system entropy increased as it processed to a final state in equilibrium with its surrounding. Entropy and temperature are directly related and exergy consumption was proportional to entropy action.