Environmental standards have recently imposed very rigorous limitations on the amounts of benzene, aromatics, and olefins, which can be found in finished gasoline. Reduction of these components could negatively affect the octane number of gasoline, so the isomerization process is gaining importance in the present refining context as an excellent safe alternative to increase the octane number of gasoline. The main aim of the naphtha isomerization unit is to modify the molecular structure of light naphtha to transform it into a more valuable gasoline blend stock, and simultaneously the benzene content is reduced by saturation of the benzene fraction. In this work, Aspen HYSYS version 12.1 is used to simulate the hydrogen once-through isomerization unit of an Egyptian refinery plant, located in Alexandria, in order to determine the properties, composition, and octane number of the isomerate product. Many potential changes are investigated in order to find the best design that efficiently raises octane number with the least amount of expense. Firstly, the plant is modified by adding one fractionator either before or after the reactor, then by adding two fractionators before and after the reactor; then the configuration which gives the highest product octane number with the highest Return on Investment (ROI) is chosen as the recommended optimum configuration. The results show that using two fractionators before and after the reactor is the best configuration. Optimization of this best configuration resulted in an increase in octane number by 7% and a decrease in the total cost by 13%.