This study aimed to assess fire–atmosphere interactions using the fully coupled Meso-NH–ForeFire system. We focused on the Pedrógão Grande wildfire (28,914 ha), which occurred in June 2017 and was one of the deadliest and most damaging fires in Portugal’s history. Two simulations (control and fully coupled fire–atmosphere) were performed for three two-way nested domains configured with horizontal resolutions of 2 km, 0.4 km, and 0.08 km, respectively, in the atmospheric model Meso-NH. Fire propagation was modeled within the innermost domain with ForeFire, which solves the fire front with a 20 m resolution, producing the heat and vapor fluxes which are then injected into the atmospheric model. A simplified homogeneous fuel distribution was used in this case study. The fully coupled experiment helped us to characterize the smoke plume structure and identify two different regimes: (1) a wind-driven regime, with the smoke plume transported horizontally southward and in the lower troposphere, and (2) a plume-dominated regime, in which the simulated smoke plume extended vertically up to upper levels, favoring the formation of a pyro-cloud. The simulations were compared, and the results suggest that the change in the fire regime was caused by an outflow that affected the main fire front. Furthermore, the fully coupled simulation allowed us to explore the change in meteorology caused by an extreme fire, namely through the development of a pyro-cloud that also induced outflows that reached the surface. We show that the Meso-NH–ForeFire system may strongly contribute to an improved understanding of extreme wildfires events and associated weather phenomena.