This paper presents the parametric optimization and performance analysis of the organic Rankine cycle (ORC) system for waste heat recovery from marine engine exhaust. The engine exhaust heat under operating conditions has been field-measured and evaluated. The thermo-economic optimization based on multi-objective evaluations is conducted numerically. This study aims to determine the optimal design evaporation temperature and condensation temperature, and to select suitable working fluids. The cooling water loop is taken into accounted for the whole ORC system. The parametric optimization with objective functions is compared. The economic objective function is defined as the ratio of net power output to total heat exchanger area, and the comprehensive objective function is determined as the weight-sum of exergy efficiency and economic objective function. The results show that there is the optimal evaporation temperature under the fixed expansion ratio in the ORC system for achieving the maximum thermal efficiency. The optimal condensation temperature for achieving the maximum economic objective function or comprehensive objective function is determined respectively. The parametric optimization with comprehensive objective function is better. With multi-objective evaluations, R141b performs the most satisfactorily with the maximum net power output of 97 kW, followed by R113 and cyclohexane, and R600a performs the least favorably. The optimized ORC system with R141b under various operating conditions is technically feasible and economically attractive. •Diesel engine parameters under various operating conditions are field-measured.•The cooling water loop for the ORC system is taken into accounted.•Optimal evaporation temperature and condensation temperature are determined.•ORC parameters and working fluids are optimized with multi-objective evaluations.