"Alachua" is a word with a mysterious origin. The Timucua were the native people of North Central Florida at the time of Spanish contact in the 16th Century, and "chua" is a Timucuan word meaning "hole." Folklore suggests the Timucua also referred to sinkholes as "chuas," and in the 17th Century, a large Spanish cattle ranch near Paynes Prairie and the Alachua Sink was identified as "La Chua." "Alachua" is therefore likely a combination of Spanish ("A la") and Timucuan ("Chua") combined together. Soon, "Alachua" referred to the entire area of North Central Florida.

The land near the present-day City of Alachua has been heavily populated by native peoples for thousands of years, as demonstrated by several archaeological sites documented on the Florida Master Site File. The Spanish established two important Catholic missions nearby to reach the Potano, the local tribe of the Timucua. San Francisco de Potano was founded in 1606 at the site of the central Potano village near San Felasco Hammock Preserve State Park, and Santa Fe de Toloca was established about 1610 a handful of miles north near the Santa Fe River. San Francisco was the first Spanish doctrina (mission with a resident priest) west of the St. John's River, and it lasted for nearly 100 years before the Spanish abandoned their Florida missions because of British attacks and the tragic decline in native population due to disease and warfare.

The American history of Alachua is deeply entwined with the history of another settlement nearby called Newnansville. In the early 1800s, the area of what would become Alachua County was inhabited and controlled by the Seminoles, a native tribe comprised of several refugee populations from Georgia, Alabama, and remaining local Timucua. Sometime between 1810 and 1820, a settlement began to form that would become known as Newnansville.

A treaty was signed in 1824 with the Seminoles, who relocated further south, near present-day Ocala. This led to more Americans settling in nascent Newnansville. Early in 1826, a post office was established, roads were built, stores were set up and a community began to emerge. This area was then called "Dell`s Post Office" in one historical document and in another it is referred to as "Dell`s Court House." It was named for the Dell brothers who first came to the Alachua area during the "Patriot War" (1812-1814) and then returned to settle. The name of this settlement was changed by the Florida Territorial Legislature to "Newnansville" in honor of Daniel Newnan, a prominent American soldier in the Patriot War. Newnansville become the Alachua County seat at that time.

Newnansville was a crossroad for several important trails through early Florida. During the Second Seminole War (1835-1842), hundreds of displaced settlers were sheltered there at Ft. Gilleland, the U.S. Army fort established in the town. As a result, Newnansville was the fourth-largest community in Florida for several years behind only St. Augustine, Pensacola and Tallahassee.

When the war was over, Newnansville became a commercial center for an area that was beginning to grow as a large number of the refugee settlers stayed and others moved in. More than one third of county voters lived in Newnansville in 1857. It likely would have remained that way had the first cross-state railroad, the Florida Railroad (connecting Fernandina to Cedar Key) not bypassed the town to the east in 1854.

A close and contentious vote was held by the County Commission to determine whether the county seat would remain in Newnansville or move to a new town to be built on the railroad.  Initially, the vote was in Newnansville's favor, but a local landowner near the rail line persuaded several people to change their mind, and the new city of Gainesville was determined to be the new county seat (one story regarding the origin of Gainesville's name is that it owes its importance to this "gain" in votes regarding the county seat).

Without access to a railroad, Newnansville declined over the next 30 years. In 1884 when the Savannah, Florida and Western Railroad bypassed it about a mile to the south, the citizens moved their businesses closer to the rail line and a new town, Alachua, began as a shipping point first called "Newnansville Station." Newnansville slowly became a ghost town.

In Alachua, F.E. Williams took advantage of the tracks running through his property. According to a March 1885 issue of the Alachua Advocate, "F.E. Williams is making an effort to get a post office established in his new town at the railroad depot. He has about 150 signatures to his petition for the same. This new town is laid off into large lots...

"Several fine houses are already completed and others are being erected. Mr. Williams will soon remove his stock of merchandise from Newnansville to his new town."   

Williams didn`t succeed in getting a post office until April 30, 1887. A hotel, livery stable, and several other stores opened. A few homes were already occupied. A grist mill and lumber mill were being erected. The Advocate reporter wrote: "Alachua will swallow up the trade of Newnansville." The prediction came true, although one man continued to operate a store in Newnansville until his death in the 1930's.