In the present work, an investigation is carried out for the assessment of the energy efficiency improvement, which can be achieved with the employment of a supercritical CO2 power cycle operating in conjunction with a marine Diesel engine. The focus is directed towards the appropriate design of the CO2 cycle, which recovers heat from three distinct waste heat sources exhibiting different temperature levels (exhaust gas, compressed scavenge air and jacket cooling water), and contributes to the propulsion load in order for the total fuel consumption to be minimized. Engineering optimization problems, based on the superstructure optimization concept, are formulated and solved, in order for the optimal configuration of the CO2 cycle and the thermodynamic states of the working fluid to be specified. For this purpose, several possible alternatives regarding the CO2 cycle are examined, and a CO2 cycle configuration resulting to improved performance of the overall system is proposed as an outcome of the optimization algorithms application. The implications of size limitations of several of the heat exchangers included in the CO2 cycle and their effects on the performance of the overall system are also assessed. The results indicate that, in comparison with a standalone operating marine Diesel engine, an efficiency enhancement in a range approximately between 6.6% and 7.25% is attainable with the best performing CO2 cycle configuration, according to the heat exchangers size limitations that may be imposed in a practical implementation of the proposed solution. Although applied for the case of a marine Diesel engine, the findings and results of the present study can also be relevant to other applications as well, in which a heavy duty turbocharged Diesel engine is used.