Performance-based design using computational and parametric optimization is an effective strategy to solve the multiobjective problems typical of building design. In this sense, this study investigates the developing process of parametric modeling and optimization of a naturally ventilated house located in a region with well-defined seasons. Its purpose is to improve its thermal comfort during the cooling period by maximizing Natural Ventilation Effectiveness (NVE) and diminishing annual building energy demand, namely Total Cooling Loads (TCL) and Total Heating Loads (THL). Following a structured workflow, divided into (i) model setting, (ii) Sensitivity Analyses (SA), and (iii) Multiobjective Optimization (MOO), the process is straightforwardly implemented through a 3D parametric modeling platform. After building set up, the input variables number is firstly reduced with SA, and the last step runs with an innovative model-based optimization algorithm (RBFOpt), particularly appropriate for time-intensive performance simulations. The impact of design variables on the three-performance metrics is comprehensively discussed, with a direct relationship between NVE and TCL. MOO results indicate a great potential for natural ventilation and heating energy savings for the residential building set as a reference, showing an improvement between 14–87% and 26–34% for NVE and THL, respectively. The approach meets the current environmental demands related to reducing energy consumption and CO2 emissions, which include passive design implementations, such as natural or hybrid ventilation. Moreover, the design solutions and building orientation, window-to-wall ratio, and envelope properties could be used as guidance in similar typologies and climates. Finally, the adopted framework configures a practical and replicable approach for studies aiming to develop high-performance buildings through MOO.