In this paper, the performance of an organic Rankine cycle with a zeotropic mixture as a working fluid was evaluated using exergy-based methods: exergy, exergoeconomic, and exergoenvironmental analyses. The effect of system operation parameters and mixtures on the organic Rankine cycle’s performance was evaluated as well. The considered performances were the following: exergy efficiency, specific cost, and specific environmental effect of the net power generation. A multi-objective optimization approach was applied for parametric optimization. The approach was based on the particle swarm algorithm to find a set of Pareto optimal solutions. One final optimal solution was selected using a decision-making method. The optimization results indicated that the zeotropic mixture of cyclohexane/toluene had a higher thermodynamic and economic performance, while the benzene/toluene zeotropic mixture had the highest environmental performance. Finally, a comparative analysis of zeotropic mixtures and pure fluids was conducted. The organic Rankine cycle with the mixtures as working fluids showed significant improvement in energetic, economic, and environmental performances.