When the "big one" hit at New Madrid, most of that part of the country was still wilderness.
Actually, it was a series of over 6,000 earthquakes between December 16, 1811 and March of 1812, with the largest three being 7.0-7.4 on December 16, 1811, 7.3–7.6 on January 23 1812, and 7.5-8.0 on February 7, 1812. They caused the Mississippi River to flow backwards, and created temporary waterfalls on the Mississippi. There was an Indian village that disappeared. They rang church bells in Boston over 1000 miles away, and were felt by Dolly Madison in the White House.
A 2008 FEMA report said that a New Madrid quake could cause "widespread and catastrophic" damage across Alabama, Arkansas, Illinois, Indiana, Kentucky, Mississippi, Missouri, and particularly Tennessee.