Dona Ana was founded in 1839 with a grant to Jose Maria Costales and 110 others. The community gave its name to Dona Ana County, and was the first county seat until 1853.
In 1851, John Russell Bartlett, for the United States, and Pedro Garcia Conde, for the Republic of Mexico, erected a monument here designating 32 degrees 22 minutes north latitude on the Rio Grande as the initial point for the official survey on the US-Mexico boundary. However, after the Gadsden Purchase, the boundary was moved south.
The Dona Ana Mountains are about 5 miles north of the village.