We have developed a new three‐dimensional seismic velocity model of the central United States (CUSVM) that includes the New Madrid Seismic Zone (NMSZ) and covers parts of Arkansas, Mississippi, Alabama, Illinois, Missouri, Kentucky, and Tennessee. The model represents a compilation of decades of crustal research consisting of seismic, aeromagnetic, and gravity profiles; geologic mapping; geophysical and geological borehole logs; and inversions of the regional seismic properties. The density, P‐ and S‐wave velocities are synthesized in a stand‐alone spatial database that can be queried to generate the required input for numerical seismic‐wave propagation simulations. We test and calibrate the CUSVM by simulating ground motions of the 18 April 2008 M_w 5.4 Mt. Carmel, Illinois, earthquake and comparing the results with observed records within the model area. The selected stations in the comparisons reflect different geological site conditions and cover distances ranging from 10 to 430 km from the epicenter. The results, based on a qualitative and quantitative goodness‐of‐fit (GOF) characterization, indicate that both within and outside the Mississippi Embayment the CUSVM reasonably reproduces: (1) the body and surface‐wave arrival times and (2) the observed regional variations in ground‐motion amplitude, cumulative energy, duration, and frequency content up to a frequency of 1.0 Hz. In addition, we discuss the probable structural causes for the ground‐motion patterns in the central United States that we observed in the recorded motions of the 18 April Mt. Carmel earthquake.