Power electronic converters have been at the center of industrial systems and various energy systems such as renewable energy systems, industrial motor drives, and grid-connected power systems. The systems face harsh conditions, making reliability an essential factor for the design. The traditional procedure for the design of converters considers the reliability of the system after the parameters have been selected for the design, making it difficult to consider the parameters of the system during the design stage. This paper proposes a reliability-oriented design optimization framework for power electronic systems operating in industrial and utility-scale applications. The proposed methodology integrates electro-thermal modeling, physics-of-failure lifetime estimation, and mission-profile-based stress evaluation within a unified multi-objective optimization framework. Junction temperature profiles and thermal cycling patterns are obtained through electro-thermal simulation under realistic operating conditions. Device lifetime is then estimated using fatigue-based models, and the resulting reliability metrics are incorporated into a multi-objective optimization algorithm that considers lifetime, efficiency, and system cost. A case study involving a 500-kW grid-connected converter demonstrates the effectiveness of the proposed approach. Simulation results show that the optimized design reduces thermal stress and increases predicted semiconductor lifetime from 6.8 years to 13.6 years while maintaining high efficiency with a moderate increase in system cost. The proposed framework provides a systematic approach for reliability-oriented design of industrial power electronic systems.