Abstract Facility layout problem (FLP) has a great impact on the efficiency of any organization. It is concerned with defining the optimal location for each facility in order to optimize the supply chain productivity. In this kind of problems, the choice of resolution approach depends on the complexity and the size of the problem. Operating theaters are generally big structures containing a lot of facilities, which makes the conception of their layout a complex problem. In the literature, exact methods are powerless when faced with problem sizes up to 18 facilities. This leads us to explore other approaches, looking for efficient solutions. This paper presents a novel approach using a multi-agents system where agents’ skills are exploited to cover a wide research space, to accelerate the decision-making process and to deal with real-life problem sizes. This decision-making tool is based on several mixed integer linear programming models for solving the FLP, and considers two types of environments with deterministic and variant patient demand. Several experiments have been performed to demonstrate the effectiveness of our approach, and several problem instances with >80 facilities have been solved in reasonable time.