The organic Rankine cycle (ORC) exhibits considerable promise in efficiently utilizing low-to-medium-grade heat. Currently, there is a range of organic fluids available in the market, and selecting the appropriate one for a specific application involves considering factors such as the cycle’s thermodynamic performance, plant size, and compatibility with turbomachinery. The objective of our study is to examine the exergetic performance of the ORC with internal heat regeneration. We analyze 12 different organic fluids to evaluate their suitability based on parameters like exergy efficiency and heat exchange area requirements. Additionally, we investigate the need for internal heat regeneration by comparing the overall exergy performance with a simpler ORC configuration. To ensure broad applicability, we consider source temperatures ranging from 150 to 300 °C, which are relevant to industrial waste heat, geothermal sources, and solar energy. For each case, we calculate specific net power output and the UA value (heat exchanger conductance) to gain insights into selecting the appropriate organic fluid for specific source temperatures. Cyclohexane, benzene, isopropyl alcohol, and hexafluorobenzene show poor exergy efficiency due to their high boiling points. Pentane and cyclopentane provides the highest exergy efficiency of 62.2% at source temperature of 300 °C, whereas pentane is found to be the most suitable at source temperatures of 200 and 150 °C with exergy efficiency of 67.7% and 61.7%, respectively. At 200 °C source temperature, RE347mcc achieves 65.9% exergy efficiency. The choice of organic fluid for a given heat source is highly influenced by its critical properties. Moreover, the normal boiling temperature of the organic fluid significantly impacts exergy destruction during the condensation process within the cycle.