Healthcare facilities are recognized as significant public architectural design, given their design complexity. Particularly in the early stages of design process, the spatial configuration cannot be overlooked and it has a significant impact on the functional performance of a building. Existing research on healthcare facility layout design focused on the methods of simulation, procedural and algorithmic approaches with limited consideration of building operational performance, or the well-being of future occupants. In light of this, this article proposes a systematic decision-support approach that combines multi-objective optimization and simulation-based occupancy performance evaluation to offer a well-performance healthcare facility layout solution. The mathematical model's purpose is to optimize building operational objectives, namely, minimizing resource transportation costs and maximizing adjacent requirements between facilities. Then the performance of the mathematical model's Pareto solutions is evaluated using a simulation module that takes user-building interactions into account. To further validate the effectiveness of our approach, we conducted a comparative experiment involving three healthcare architects in the design of a surgical ward layout. Results indicate that the proposed approach can assist architects in achieving a balance between efficiency and safety in healthcare facility layout design, resulting in a more occupant-centric building design. Moreover, this systematic approach provides the theoretical basis on describing how to integrate the widely researched models for architectural layout planning and occupancy performance evaluation.