Understanding how sedimentary basins respond to seismic-wave energy generated by large earthquake events is a significant concern for seismic-hazard estimation. This study explores the use of microtremors, or ambient noise, for evaluating strong-motion site effects. The study focuses on the Mississippi Embayment in the New Madrid Seismic Zone, where widespread liquefaction and ground failure occurred during the 1811–1812 earthquake sequence. Spectral analyses of microtremor data at sites representing different environments of deposition (and sedimentary facies), different embayment thicknesses, and varying liquefaction susceptibility show correlations between (1) calculated vulnerability indices and evidence of liquefaction, (2) sediment thickness and fundamental resonant frequency, and (3) subsurface stratigraphic boundaries and observed peaks in horizontal-to-vertical spectral ratios. Results of the study suggest that the microtremor method could be helpful in identifying those areas most vulnerable to ground amplification in intraplate sedimentary basins, where large earthquakes are infrequent but potentially damaging.