The distinctly need for developing energy efficient and functional structural designs, demands the adoption of multidisciplinary techniques that will guarantee constructions’ integrity. Towards this objective, engineers and scientists employ Computational Fluid Dynamic (CFD) tools and optimisation techniques, in order to first predict the physical phenomena occurring in the built environment and in sequence to find optimum solutions that will assist the conceptual design phase. In the current study, a methodology to conduct design optimisation studies is demonstrated, using coupled CFD and Response Surface Methodology (RSM) meta-model based optimisation techniques. Regarding the assessment of the natural ventilation performance of a cross ventilated building, the design optimisation of the window openings was performed. The results revealed the ability to obtain locally optimal solutions, along with a further insight on the influential role of the design parameters in design’s response. The methodology was validated with wind tunnel experiments and the optimisation results were verified, confirming the competence for conducting similar design optimisation studies.