Santa Anna is at the intersection of the Atchison, Topeka and Santa Fe Railway, U.S. highways 283, 67, and 84, and Farm Road 1176 eight miles southeast of Coleman in southeast central Coleman County. The town was named for the twin mountains located just north of the community, which were in turn named for Santa Anna, a Comanche chief. The peaks served as a landmark to early surveyors and settlers. Camp Colorado, occupied by the United States Army from 1857 to 1861, was ten miles north of the site. Texas Rangersqv were also stationed in the vicinity and used the peaks as an observation post. Duke Jackson brought cattle into the area and built the first cabin at the site in 1860.

The town's population remained static through the 1960s, revived in the 1970s, reached 1,535 in 1980, and then fell to 1,249 in 1990. In the 1990s town industries included the Stempel office furniture plant and Art Fabrics. Efforts were underway to restore and revitalize the downtown area. The population dropped to 1,081 in 2000.