To meet the current challenges of sustainable development, the environmental assessment of urban projects is essential to bring substantial arguments of their performances. To do so, the Life Cycle Assessment (LCA) starts to be applied to large systems such as neighborhoods. The advantages of this methodology (e.g. evaluating pollution transfers, considering a wide range of local or global impacts, etc.) make it a good candidate for an efficient performance assessment. Nevertheless districts are highly complex systems, their scope includes various sectors such as construction, transport, energy, water and waste management. Existing tools have to be adapted in order to simulate all these sectors in a systemic way. To achieve such an ambitious goal, the first step is to harmonize the analytic simulation of district components. The aim of this work is to identify key elements that may improve the systemic simulation of districts and thus ensure a better assessment of their environmental performances. The work is based on the study of a four-hectare project located in the Paris region. Simulations of project’s associated mobility, buildings and district energy consumptions and waste and water management have been combined to provide global environmental evaluation based on the LCA methodology. This study shows the relevance of adopting multi-domain simulations in order to evaluate relative contributions of the system’s different components. However, to enhance the coherence of holistic evaluation, further work is needed to harmonize methodological choices such as allocation criteria and definition of functional units. Also this study underlines the need to use consistent and harmonized assumptions (e.g. for usage scenarios) and to work at different scales for network-based activities (e.g. mobility) in order to take into account global and local interactions. To overcome these challenges potential solutions are proposed, their feasibility and perspectives are presented in the context of urban planning projects.