We employed a 3D velocity model and 3D wave propagation code to simulate long-period ground motions in the upper Mississippi embayment. This region is at risk from large earthquakes in the New Madrid seismic zone (NMSZ) and observational data are sparse, making simulation a valuable tool for predicting the effects of large events. We undertook these simulations to estimate the magnitude of shaking likely to occur and to investigate the influence of the 3D embayment structure and finite-fault mechanics on ground motions. There exist three primary fault zones in the NMSZ, each of which was likely associated with one of the main shocks of the 1811–12 earthquake triplet. For this study, three simulations have been conducted on each major segment, exploring the impact of different epicentral locations and rupture directions on ground motions. The full wave field up to a frequency of 0.5 Hz is computed on a 200 × 200 × 50-km3 volume using a staggered-grid finite-difference code. Peak horizontal velocity and bracketed durations were calculated at the free surface. The NMSZ simulations indicate that for the considered bandwidth, finite-fault mechanics such as fault proximity, directivity effect, and slip distribution exert the most control on ground motions. The 3D geologic structure of the upper Mississippi embayment also influences ground motion with indications that amplification is induced by the sharp velocity contrast at the basin edge.