Medium and low-temperature solar thermal power generation, integrating parabolic trough collectors with transcritical carbon dioxide (CO2)-based mixture power cycles, is explored for enhanced solar energy utilization and improved efficiency. This study assesses the feasibility of parabolic trough concentrated solar power plants utilizing transcritical CO2-based mixtures, considering energy output, efficiency, economics, and environmental (4E) aspects. Seven candidate organic working fluids (R32, R134a, R152a, R1234yf, R161, R290, and R1270) are evaluated within a two-layer decision-making framework based on multi-objective optimization. Results indicate a significant performance improvement with an increased mass fraction of the organic working fluid. Particularly, systems employing CO2/R32 or CO2/R161 demonstrate superior overall performance compared to those with other CO2-based mixtures. Under the base case (at a hot tank temperature of 350 °C), the CO2/R32 (0.3/0.7 wt%) system achieves the maximum energy output (355.22 kW), while the CO2/R161 (0.3/0.7 wt%) system attains the highest efficiency with the lowest levelized cost of electricity and CO2 emissions (9.78%, 0.576 $/kW·h, and 0.0328 kg/kW·h, respectively). Exergy analysis emphasizes the predominant role of the solar collector in exergy destruction (approximately 70%), with the CO2/R161 (0.3/0.7 wt%) system yielding the highest exergy efficiency (14.96%). Across a hot tank temperature range of 250–350 °C and an organic fluid mass fraction of 0.3–0.7, the working fluids are generally ranked as CO2/R161, CO2/R32, CO2/R152a, CO2/R1270, CO2/R134a, CO2/R290, and CO2/R1234yf in terms of the 4E aspects via a multi-objective optimization decision-making framework.