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During the Civil War, Union and Confederate forces fought in the area in 1864 in the Battle of Tupelo. Designated the Tupelo National Battlefield, the war site is administered by the National Park Service (NPS). In addition, the Brices Cross Roads National Battlefield, about ten miles north, commemorates another Civil War site.

After the war, a cross-state railroad for northern Mississippi was constructed through the town, which encouraged industry and growth. With expansion, the town changed its name to Tupelo, in honor of the battle. It was incorporated in 1870.

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