In the framework of process safety studies, consequence assessment of accidental scenarios is a crucial step affecting the eventual risk profile associated with the facilities under analysis. Conventional models used for consequence assessment are based on integral models, and may not be adequate to cope with the dynamic evolution of accidental scenarios and their three‐dimensional features. On the other hand, consequence assessment models based on computational fluid dynamics (CFD) approaches are promising to cope with complex scenarios and environments, but setting the simulation introduces relevant uncertainties associated with both the input data, assumptions, and with the modelling of physical effects involved. In the present study, uncertainty quantification (UQ) techniques are applied to support advanced safety studies based on CFD simulations of hazardous gas dispersion. Firstly, the accidental scenarios are characterized by defining release scenarios and conditions and quantifying source terms using integral models. At the same time, input meteorological data are gathered. This enables the development of high‐fidelity CFD simulations of gas dispersion based on different input sets and eventually the implementation of UQ techniques. The generalized polynomial chaos (gPC) expansion is employed to obtain hazardous gas concentration based on the variation of wind direction and speed. The present method is applied for the analysis of a real plant featuring a complex layout. The results show the advantages of the present approach by quantifying the influence of meteorological conditions and providing indications for supporting the development of protection systems and emergency measures.