The first inhabitants of the area were the Quapaw Indians, who settled in what would become Mississippi County as late as 1720. After they were forced to leave their land, the tribe settled on a nearby reservation before they were removed to the Indian Territory in what is now Oklahoma.
The first post office in what would become Blytheville was founded by Henry T. Blythe, a Methodist circuit rider in 1879. In 1880, the Reverend Blythe developed a plan for the town and by 1881, he began to sell land lots. The first phase of the local economy centered around lumber. The city of Blytheville was incorporated in May 1889. The first county courthouse was built in 1902 and the present building in 1919.
In 1942, the army opened an airfield outside of Blytheville to train pilots. It was closed at the end of World War II, but reopened in 1955 as Blytheville Air Force Base. It was renamed Eaker Air Force Base in 1988 and closed in 1992.
The former Cotton Boll Technical Institute, a few miles south in Burdette, and Mississippi County Community College, the first all solar-powered college in the nation, are now Arkansas Northeast College.
Today, Blytheville is regarded as one of the centers of steel production in the United States. Nucor Steel has two mills in the Blytheville area.
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