The settlement at Alachua is dated back to 1884. The railroad had bypassed nearby Newnansville and Alachua was the nearest place fit for constructing buildings on (the area has a lot of sinkholes in its limestone karst topography). Anglophone settlers had been in the area since the 1820's but a couple wars with the Seminoles had made things hard for settlers. For a while, eight different military forts were in operation in Alachua County in an effort to protect the settlers.

In 1854, a railroad was built connecting Fernandina (on the northeast Atlantic Coast) with Cedar Key (on the Gulf). It bypassed the significantly large town of Newnansville and led to the establishment of Gainesville a few miles to the south. The fortunes of Newnansville declined slowly for the next 30 years. Then with the construction of the Savannah, Florida and Western Railroad passing by about one mile south of Newnansville, that was the end: businesses packed and moved closer to the railroad siding at Alachua. Alachua got its first official post office in 1887.

These days, Alachua is primarily an agricultural and retirement center, and a bedroom community for the businesses and schools of nearby Gainesville. The population is up almost 49% since 2000.