The computational fluid dynamics-based design of next-generation aeronautical combustion chambers is challenging due to many geometrical and operational parameters to be optimized and several sources of uncertainty that arise from numerical modeling. The present work highlights the potential benefits of exploiting Bayesian uncertainty quantification at the preliminary design stage. A prototypical configuration of an acetone/air spray swirling jet is investigated through an Eulerian–Lagrangian method under non-reactive conditions. Two direct numerical simulations (DNSs) provide reference data, coping with different vortex breakdown states. Consequently, a set of Reynolds-averaged Navier–Stokes simulations is conducted. Polynomial chaos expansion (PCE) is adopted to propagate the uncertainty associated with the spray dispersion model and the turbulent Schmidt number, delivering confidence intervals and the sensitivity of the output variance to each uncertain input. Consequently, the most significant sources of modeling uncertainty may be identified and eventually removed via a calibration procedure, thus making it possible to carry out a combustion chamber optimization process that is no longer affected by numerical biases. The uncertainty quantification analysis in the current study demonstrates that the spray dispersion model slightly affects the fuel vapor spatial distribution under vortex breakdown flow conditions, compared with the output variance induced by the selection of the turbulent Schmidt number. As a result, additional high-fidelity experimental and numerical campaigns should exclusively address the development of an ad hoc model characterizing the spatial distribution of the latter in the presence of vortex breakdown phenomenology, discarding any effort to improve the spray dispersion formulation.