Heterogeneous integration technology makes possible the integration of multiple separately manufactured components into a single higher level assembly with enhanced functionality and improved operating characteristics. Various types of advanced heterogeneous packages are available, including 2.5-D integrated circuit (IC), fan-out chip on substrate (FOCoS) chip-first, and FOCoS chip-last. This study constructs a nonlinear simulation technique (3-D simulation model) to explore the warpage, extreme low-<inline-formula> <tex-math notation="LaTeX">$k$ </tex-math></inline-formula> (ELK) interconnect stress, redistribution layer (RDL) trace stress, and board-level solder joint reliability of all three packages. The validity of the simulation model is confirmed by comparing the numerical results for the in-plane dimensional change of an FOCoS chip-last package with the experimental observations over the temperature range of 30 °C–260 °C. The thermal performance (i.e., junction-to-ambient thermal resistance) of the three packages is then examined and compared. Finally, <inline-formula> <tex-math notation="LaTeX">$2^{5}$ </tex-math></inline-formula> factorial designs with the analysis of variance (ANOVA) are conducted to examine the effects of the main structural design parameters of the FOCoS chip-last package on its thermomechanical reliability under typical thermal loading conditions. It is shown that a thinner polyimide (PI) layer is beneficial in improving the package reliability by minimizing the coefficient of temperature expansion (CTE) mismatch between the PI layer and the RDL trace, respectively.