Hospitals are known as functionally complex buildings in various ways, namely due to their non-trivial spatial connectivity requirements. A spatial configuration has an impact on human behavior, human movement patterns and should match with the operational logic of the buildings. In hospitals, there are several typical problems that can be attributed to the configuration of the building, namely the inefficient circulation of medical staff, difficult way-finding for visitors, lengthy and complex procedures for patients, long walking times, privacy, hygiene issues and so on. This Ph.D. research aims to develop a computational design methodology for configurational layout optimization of hospital buildings concerning physical matters & human factors, which are directly attributable to the layout/configuration of the hospital. In the optimization models, the considered performance indicators are related with patients (e.g. ease of way-finding), staff (e.g. average walking-time), and operations (e.g. fitness for workflows). Two case studies are studied here as (1) reconfiguration of existing hospitals; and (2) designing the new hospitals by focussing on “layout planning” and “corridor design”. The developed models are programmed in the form of design tool-kits for supporting conceptual design phases. Effectively, this project presents an interdisciplinary methodological framework that can tackle hospital layout design problems by integrating Computational Design workflows, Graph Theory techniques, Operations Research, and Computational Intelligence into the field of Architectural Space Planning.