We used WRF-Chem to simulate ash transport from eruptions of Chile’s Calbuco volcano on 22–23 April 2015. Massive ash and SO2 ejections reached the upper troposphere, and particulates transported over South America were observed over Argentina, Uruguay, and Brazil via satellite and surface data. Numerical simulations with the coupled Weather Research and Forecasting–Chemistry (WRF-Chem) model from 22 to 27 April covered eruptions and particle propagation. Chemical and aerosol parameters utilized the GOCART (Goddard Chemistry Aerosol Radiation and Transport) model, while the meteorological conditions came from NCEP-FNL reanalysis. In WRF-Chem, we implemented a more efficient methodology to determine the Eruption Source Parameters (ESP). This permitted each simulation to consider a sequence of eruptions and a time varying ESP, such as the eruption height and mass and the SO2 eruption rate. We used two simulations (GCTS1 and GCTS2) differing in the ash mass fraction in the finest bins (0–15.6 µm) by 2.4% and 16.5%, respectively, to assess model efficiency in representing plume intensity and propagation. Analysis of the active synoptic components revealed their impact on particle transport and the Andes’ role as a natural barrier. We evaluated and compared the simulated Aerosol Optical Depth (AOD) with VIIRS Deep Blue Level 3 data and SO2 data from Ozone Mapper and Profiler Suite (OMPS) Limb Profiler (LP), both of which are sensors onboard the Suomi National Polar Partnership (NPP) spacecraft. The model successfully reproduced ash and SO2 transport, effectively representing influencing synoptic systems. Both simulations showed similar propagation patterns, with GCTS1 yielding better results when compared with AOD retrievals. These results indicate the necessity of specifying lower mass fraction in the finest bins. Comparison with VIIRS Brightness Temperature Difference data confirmed the model’s efficiency in representing particle transport. Overestimation of SO2 may stem from emission inputs. This study demonstrates the feasibility of our implementation of the WRF-Chem model to reproduce ash and SO2 patterns after a multi-eruption event. This enables further studies into aerosol–radiation and aerosol–cloud interactions and atmospheric behavior following volcanic eruptions.