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Sikeston is located mostly in extreme southern Scott County, though a small portion of it does lie in extreme northern New Madrid County. The latter consists chiefly of businesses near the intersection of U.S. Routes 60 and 61, with the large majority of residential units on the north side of the line in Scott County. The exact coordinates are 36°52’46”N, 89°35’07”W.

Sikeston is located mostly in extreme southern Scott County, though a small portion of it does lie in extreme northern New Madrid County. The latter consists chiefly of businesses near the intersection of U.S. Routes 60 and 61, with the large majority of residential units on the north side of the line in Scott County. The exact coordinates are 36°52’46”N, 89°35’07”W.

The city has a total area of 17.48 square miles, all but 0.16 square miles of it land, and an average elevation of 328 feet. This is slightly higher than the surrounding region, as most of Sikeston is located on a very low, sandy ridge, known locally as "Sikeston Ridge" and superior to the nearby bottomlands for building purposes.

The city has a total area of 17.48 square miles, all but 0.16 square miles of it land, and an average elevation of 328 feet. This is slightly higher than the surrounding region, as most of Sikeston is located on a very low, sandy ridge, known locally as "Sikeston Ridge" and superior to the nearby bottomlands for building purposes.<ref>https://web.archive.org/web/20120125061959/http://www.census.gov/geo/www/gazetteer/files/Gaz_places_national.txt</ref>

A number of major highways meet in or near Sikeston. Interstate 55 runs just to the east, passing through the adjacent town of Miner, while the city is also the southern terminus of Interstate 57. Three U.S. Highways also meet in Sikeston: U.S. Route 60 skirts the southern edge of the city; U.S. Route 61 (Kingshighway) runs through it from north to south; and U.S. Route 62, entering Sikeston from the east as Malone Avenue, joins with Route 61 at Kingshighway and continues south.

A number of major highways meet in or near Sikeston. Interstate 55 runs just to the east, passing through the adjacent town of Miner, while the city is also the southern terminus of Interstate 57. Three U.S. Highways also meet in Sikeston: U.S. Route 60 skirts the southern edge of the city; U.S. Route 61 (Kingshighway) runs through it from north to south; and U.S. Route 62, entering Sikeston from the east as Malone Avenue, joins with Route 61 at Kingshighway and continues south.