Popocatépetl is one of Mexico’s most active volcanoes threatening a densely populated area that includes Mexico City with more than 20 million inhabitants. The destructive potential of this volcano is demonstrated by its Late Pleistocene–Holocene eruptive activity, which has been characterized by recurrent Plinian eruptions of large magnitude, the last two of which destroyed human settlements in pre-Hispanic times. Popocatépetl’s reawakening in 1994 produced a crisis that culminated with the evacuation of two villages on the northeastern flank of the volcano. Shortly after, a monitoring system and a civil protection contingency plan based on a hazard zone map were implemented. The current volcanic hazards map considers the potential occurrence of different volcanic phenomena, including pyroclastic density currents and lahars. However, no quantitative assessment of the tephra hazard, especially related to atmospheric dispersal, has been performed. The presence of airborne volcanic ash at low and jet-cruise atmospheric levels compromises the safety of aircraft operations and forces re-routing of aircraft to prevent encounters with volcanic ash clouds. Given the high number of important airports in the surroundings of Popocatépetl volcano and considering the potential threat posed to civil aviation in Mexico and adjacent regions in case of a Plinian eruption, a hazard assessment for tephra dispersal is required. In this work, we present the first probabilistic tephra dispersal hazard assessment for Popocatépetl volcano. We compute probabilistic hazard maps for critical thresholds of airborne ash concentrations at different flight levels, corresponding to the situation defined in Europe during 2010, and still under discussion. Tephra dispersal mode is performed using the FALL3D numerical model. Probabilistic hazard maps are built for a Plinian eruptive scenario defined on the basis of geological field data for the “Ochre Pumice” Plinian eruption (4965 14C yr BP). FALL3D model input eruptive parameters are constrained through an inversion method carried out with the semi-analytical HAZMAP model and are varied by sampling them using probability density functions. We analyze the influence of seasonal variations on ash dispersal and estimate the average persistence of critical ash concentrations at relevant locations and airports. This study assesses the impact that a Plinian eruption similar to the Ochre Pumice eruption would have on the main airports of Mexico and adjacent areas. The hazard maps presented here can support long-term planning that would help minimize the impacts of such an eruption on civil aviation.