The thermal and moisture management of electronic enclosures are fields of high interest in recent years. It is now generally accepted that the protection of electronic devices is dependent on avoiding critical levels of relative humidity (typically 60–90%) during operations. Leveraging the development of rigorous calibrated CFD models as well as simple predictive numerical tools, the current paper tackles the optimization of critical features of a typical two-chamber electronic enclosure. The progressive optimization strategy begins the design parameter selection by initially using simpler equivalent RC-circuit models for concentration of water vapor and temperature in the electronic enclosure. After reducing the potential parameter-value space for the critical features using the RC-approach, the optimization strategy uses simpler 2D CFD models of temperature and moisture transport to further focus the parameter-value space, before shifting to 3D CFD models for final evaluations and verification. The approach results in a system capable of predicting optimum design features for the thermal and moisture management of electronic enclosures in a time-efficient and practically implementable manner.