In this paper, the characteristics of polymeric packaging materials for Pre-mold QFN type CMOS Image Sensor (CIS) have been carefully investigated. Hygro-mechanical property, the coefficient of moisture expansion (CME) for different materials was measured through Thermal Mechanical Analysis (TMA) and Thermal Gravitational analysis (TGA) at given humidity and temperature. Moisture absorption/desorption diffusivity were determined under Arrhenius behavior. The transient moisture diffusion analysis described by Fick's equation is performed to evaluate the overall moisture distribution. In accordance with the JEDEC pre-conditioning standard JESD22-A120, reliability and thermal design were carried out due to mismatch of the coefficient of thermal expansion (CTE) and CME for multi-material package of CIS. A threedimensional solid model of CIS based on finite element ANSYS software is developed to predict the thermal-induced strain, hygroscopic swelling deformation and the residual thermo-hygro-mechanical stress distributions. A series of comprehensive parametric studies were conducted in this research.