In recent years, the use of fan-out packaging solutions has boomed in semiconductor-related fields. There are primarily two versions used for mass production: wafer level and panel level. In this research, a glass substrate was used in the design of a fan-out wafer-level package (FO-WLP) and simulations were conducted to predict the reliability of the solder joints. The advantages of glass substrates are their excellent electrical properties, good mechanical rigidity, flatness, and adjustable coefficient of thermal expansion. To verify the robustness of the simulations, a FO-WLP test vehicle was designed, manufactured, and tested under JEDEC thermal cycling condition. In this study, the simulation results were used in an empirical equation to estimate the reliability of the FO-WLP under accelerated thermal-cycling conditions. After simulation validated by experiments, parametric simulations of different design factors can be performed. Using this methodology, we developed a reliable finite element analysis procedure. Thus, structural optimization of the FO-WLP was possible via simulations using various design factors to improve its reliability. The simulation results indicate that a suitable combination of upper, lower pad sizes and the thickness of buffer layer could significantly enhance the reliability life of FO-WLP, and that designers should devote greater attention to these factors to achieve better long-term reliability performance.