Once apart of a "No Man's Land" between Mexico and the United States, Old Mesilla is now a part of New Mexico. After the Treaty of Guadalupe Hidalgo, the United States claimed territory previously apart of Mexico. Both countries agreed on treaty boundaries, but map inaccuracies led to later disagreements. By 1850, Mesilla had its first permanent residents and became an established colony.

Apache and other nomadic native tribes had lived in the Mesilla vicinity prior too it becoming a colony, and residents of the town sometimes came under attack from Apache people. A Mesilla Guard comprised of men from each household and the newly established Fort Fillmore protected colonists and traders from attack. Also, the town centered around a Plaza as a defense mechanism.

The Plaza was the location of the raising of the American Flag by Fort Fillmore troops after the United States and Mexico rectified the boundary dispute with the Gadsden Purchase. Mesilla and Fort Fillmore fell to Confederate troops who took over the town and made it the capital of the Confederate's Arizona Territory until the end of the war.

Because of its location and protection it guaranteed from area forts, Mesilla became a town along different trade routes. The El Camino Real and the Butterfield Stage Route both passed through the town, so many traders and outsiders helped to economically benefit Mesilla. The famous outlaw Billy the Kid ran into bad luck in Mesilla. His trial resulted in a sentence to hang.

Today the town contains around 2,000 residents and many places are apart of the National Historic Register.