The thermal efficacy of thermal interface material (TIM) is highly dependent on its ability to adhere to the surfaces of interest. Any delamination of the TIM from the die or the lid will increase the local thermal resistance and, thus, will reduce the overall effectiveness of the TIM. Although significant amount of work has been done on understanding the thermal and moisture effects of various polymer materials used in microelectronic package assemblies, very limited work has been done to study the effect of temperature and moisture on TIM delamination. In this paper, a sequential hygro-thermal-mechanical finite-element model has been developed to mimic the loadsteps associated with package assembly as well as moisture soaking under /85RH over 500 h. The predictions from the models have been validated with a wide range of experimental data including laser Moiré data for thermomechanical loading and digital image correlation data for hygro-thermo-mechanical loading. Weight gain and coordinate-measurement machine have been used to characterize moisture diffusivity and moisture expansion coefficient of various polymer materials in the package assembly. The developed models show the evolution of normal strain in TIM during various loadsteps and provide important insight into the potential for TIM delamination under package assembly process and moisture soaking. Thus, the models can be used for developing various designs and process steps for reducing the chances for TIM delamination.