The historic district is nearly coterminous with the City of Nauvoo as it was incorporated in 1840, but it also includes the Pioneer Saints Cemetery (40°32′13″N 91°21′03″W / 40.5369°N 91.3507°W / 40.5369; -91.3507 (Old Nauvoo Burial Grounds)), the oldest Mormon cemetery in the area, which is outside the town boundary.

The city's basic plan is still discernible despite the many modern intrusions, and there are a wealth of historical archaeological sites related to the early Latter Day Saint settlement period, including the site of the Nauvoo Temple, which occupied a prominent location in the city; it was burned in 1848 and its remains were leveled by a tornado in 1865.

Due to the large influx of Mormons, Nauvoo became Illinois's largest city for a brief period in the 1840s.

Despite this, it lacked a distinct commercial center, consisting mainly of residences laid out on broad streets on a rectangular grid.

After assuming the leadership of the Reorganized Church of Jesus Christ of Latter Day Saints (Community of Christ) in 1860 Joseph Smith III living in the Smith Family Homestead, would lead that portion of the Latter Day Saint Movement from Nauvoo until he relocated to Plano, Illinois in 1866.