Santa Anna is on the Fayette county line at the Colorado River, Crier Creek, and State Highway 71 in northwestern Colorado County. The first settlers in the area were the families of Joseph Duty, one of Stephen F. Austin's Old Three Hundred, who received title to a league of land on July 19, 1824, and Jesse Burnam, who received his title on August 16 of the same year. Through the community passed the La Bahía branch of the Spanish road that connected Nacogdoches, San Antonio, and La Bahía. The Duty family moved up the Colorado River. Burnam built a trading post and ferry across the Colorado River nearby, and these prospered until March 19, 1836, when the ferry was destroyed by the Texas Army under Sam Houston in its retreat from Gonzales. Following the Texas Revolution Burnam also moved, and most of the local farmland reverted to native vegetation.
The wave of immigration that followed the Civil War brought many new settlers to the area from Germany and Czechoslovakia. Of the more than 100 families that claimed residence in the community, the majority were tenant farmers and sharecroppers who produced cotton and corn in the rich bottomland along the river. In the early 1900s a school was established, and it flourished for almost fifty years, until it was consolidated with the Columbus Independent School District.
The loss of cotton as a crop during the 1950s also led to a loss of people and small farms. In 1985 about twenty families still claimed ties to the Santa Anna community. Many of these had jobs elsewhere, and the land was used primarily for pasturing cattle and raising hay and pecans.