This paper presents a coupled computational fluid dynamics (CFD) and computational structural dynamics (CSD) methodology for simulating explosively loaded reinforced concrete structures. The approach is validated through comparisons with experimental data from a full-scale, four-story building test. The simulations predict blast wave propagation, structural response, debris generation, and internal and external pressure fields. A bare plastic-explosive reference test is used to evaluate the coupled CFD–CSD framework, which models explosive initiation and detonation, air-blast loading, debris impact, structural failure, and progressive collapse. The CFD solver computes the compressible Euler and Reynolds-Averaged Navier–Stokes equations on an unstructured tetrahedral mesh, while the CSD solver models large-deformation, large-strain structural behavior using variational multiscale stabilization. The solvers are coupled using a loose-coupling strategy with projection-based data transfer at the fluid–structure interface. A hybrid MPI/OpenMP parallelization enables efficient large-scale simulations. Numerical results show good agreement with experiments. Predicted failure mechanisms, collapse progression, debris distributions, and pressure decay trends closely match measurements, demonstrating the capability of the proposed methodology for realistic blast-response simulations.