We performed a suite of numerical simulations based on the 1811–1812 New Madrid seismic zone (NMSZ) earthquakes, which demonstrate the importance of 3D geologic structure and rupture directivity on the ground-motion response throughout a broad region of the central United States (CUS) for these events. Our simulation set consists of 20 hypothetical earthquakes located along two faults associated with the current seismicity trends in the NMSZ. The hypothetical scenarios range in magnitude from M 7.0 to 7.7 and consider various epicenters, slip distributions, and rupture characterization approaches. The low-frequency component of our simulations was computed deterministically up to a frequency of 1 Hz using a regional 3D seismic velocity model and was combined with higher-frequency motions calculated for a 1D medium to generate broadband synthetics (0–40 Hz in some cases). For strike-slip earthquakes located on the southwest–northeast-striking NMSZ axial arm of seismicity, our simulations show 2–10 s period energy channeling along the trend of the Reelfoot rift and focusing strong shaking northeast toward Paducah, Kentucky, and Evansville, Indiana, and southwest toward Little Rock, Arkansas. These waveguide effects are further accentuated by rupture directivity such that an event with a western epicenter creates strong amplification toward the northeast, whereas an eastern epicenter creates strong amplification toward the southwest. These effects are not as prevalent for simulations on the reverse-mechanism Reelfoot fault, and large peak ground velocities (>40 cm=s) are typically confined to the near-source region along the up-dip projection of the fault. Nonetheless, these basin response and rupture directivity effects have a significant impact on the pattern and level of the estimated intensities, which leads to additional uncertainty not previously considered in magnitude estimates of the 1811–1812 sequence based only on historical reports. The region covered by our simulation domain encompasses a large portion of the CUS centered on the NMSZ, including several major metropolitan areas. Based on our simulations, more than eight million people living and working near the NMSZ would experience potentially damaging ground motion and modified Mercalli intensities ranging from VI to VIII if a repeat of the 1811–1812 earthquakes occurred today. Moreover, the duration of strong ground shaking in the greater Memphis metropolitan area could last from 30 to more than 60 s, depending on the magnitude and epicenter.