The shift toward renewable energy has drawn significant attention to zeotropic mixtures in the organic Rankine cycle (ORC). However, synthetic zeotropic mixtures are detrimental to the environment due to high global warming potential. In this context, this study explores the potential of natural zeotropic binary mixtures as an alternative to synthetic zeotropic mixtures in a transcritical ORC system. The performance of two natural zeotropic mixtures and three synthetic zeotropic mixtures (hydrofluorocarbons, hydrofluoroolefins) are analyzed and compared using turbine inlet pressure and carbon dioxide (CO2) concentration as objective functions. The comprehensive thermodynamic analysis focuses on energy (first‐law) and exergy (second‐law) efficiencies, heat transfer, environmental performance, and economic aspects. The thermal and exergy efficiencies of the natural zeotropic mixture consistently outperform other mixtures by a maximum of 8% and 18%, respectively, for the conditions studied. The net power‐to‐environmental impact ratio of natural zeotropic mixture outweighs other zeotropic mixtures by more than 50%. The heat transfer analysis also favors natural zeotropic mixture at CO2 concentrations below 60% while maintaining cost parity with synthetic zeotropic mixtures. The results emphasize a holistic approach involving performance, heat transfer, environmental impact, and cost as parameters while choosing zeotropic mixtures for sustainable energy harvesting.