A combined effect of moisture diffusion, heat transfer, and hygro-thermo-vapor pressure modeling for pre-mold QFN CMOS Image Sensor (CIS) package has been developed in this study. Hygroscopic swelling properties such as saturation, coefficient of moisture expansion (CME) and activation energy can be extracted through TMA (Thermal Mechanical Analysis) and TGA (Thermal Gravitational Analysis) instruments. Fick’s second law of transient diffusion is solved by using finite element analysis (FEA) to evaluate the overall moisture distributions. With obtained experimental data, a three-dimensional FEA CIS model using the “thermal-wetness” technique is developed to predict the moisture absorption, moisture desorption, temperature distributions, hygro-thermo-vapor pressure mechanical coupled effect and the residual stress distributions at JEDEC pre-conditioning standard JESD22-A120.