The area was once the domain of the Timucuan peoples, two tribes of which existed in the Palatka region under chiefs Saturiwa and Utina.

However, infectious disease that came with European contact and war devastated the tribes, and they were extinct as organized peoples by the mid-18th century.

Some of their survivors merged with other tribes; other Timucua evacuated with the Spanish to Cuba in 1763, when Spain ceded Florida to Great Britain in an exchange of interests after the latter's defeat of France in the Seven Years' War.

In 1767, Denys Rolle (1725–1797), an English gentleman and philanthropist, established Rollestown on the east bank of the St. Johns River, at the head of deepwater navigation.

He recruited settlers off the streets of London to serve as indentured servant/workers: they included paupers, vagrants, pickpockets and "penitent prostitutes".

He used them as workers to tend livestock, such as chickens, hogs, goats and sheep, or cultivate and process cotton, indigo, citrus and turpentine for export to Europe.

When Spain resumed control of Florida in 1783 for a period, Rolle abandoned the colony and chartered a ship to carry his household belongings, livestock and slaves to a 2,000-acre (8.1 km2) estate on Great Exuma in the Bahamas.

When the government attempted to relocate the tribe to the west of the Mississippi as part of Indian Removal starting in 1833, the Second Seminole War began.

During the 1850s, Florida in general and Pilatka in particular gained a reputation as a seasonal haven for invalids and others escaping severe northern winters.

One visitor wrote that amusements included "sailing, fishing, rowing, walking, riding in buggies and on horseback, whist, euchre, backgammon and hunting".

Mary Boyd pleaded with Union Commander Maxwell Woodhull to spare Pilatka, assuring him that the horse soldiers were not residents.

Sánchez became upset when their father was falsely accused of being a Confederate spy and imprisoned by Union Army soldiers.

John Jackson Dickison, surprised and captured the Union troops on the day of the supposed raid in what is known as the Battle of Horse Landing.

In 1893, A. E. and H. S. Wilson of Saginaw, Michigan bought the Noah J. Tilghman & Son sawmill, which processed cypress lumber.

The area's warm and humid climate is caused primarily by its proximity to the Gulf Stream, which flows off the east coast of Florida.

This significance was due to its location at the end of an expansive portion of waterway at the divide between the upper and lower St. Johns River.

The decline of waterborne travel in Northeast Florida, and the United States in general, ultimately reduced the importance of tourism in the city.

Only 7.1% of Palatka's labor force works in arts, entertainment, recreation, accommodation, and food services,[17] compared to Florida's 15.5% across tourist related industries.

[18] In recent years, the Putnam County government has adopted policies focused on facilitating Ecotourism in the region.

[20][21] If progress continues, and ecotourism creates a vibrant local economy, economic incentives could drive further preservation of the natural habitats, benefitting the environment as a whole.

Regionally, the employment numbers of Palm Coast have been hit hardest; the bedroom community has an unemployment rate currently at 16.6%.

Due to the historical importance of Palatka as a southeastern interior port, much of the urban development is oriented toward the riverfront.

The eastern sections of the city, which include downtown and the historic districts, are characterized by a gridded street system.

The library is a fusion of Prairie School and Art Deco, and is listed on the National Register of Historic Places.

[31] Though there are no discernible architectural styles in the outgrowth areas, a notable building technique has been used in the construction of the 23,000-square-foot (2,100 m2) Children's Reading Center Charter School.

[34] Palatka uses the commission-manager form of municipal government, with all governmental powers resting in a legislative body called a commission.

[37] The Palatka campus serves as the administrative center, it also houses the Florida School of the Arts and the local St. Leo University branch.

The river is no longer a primary means of passenger transportation, but remains of strategic importance in the movement of goods and services.

The Brevi Bus was created to handle the rugged terrain and unpaved roads of rural Putnam County.

The Palatka Amtrak station is a historic Atlantic Coast Line Railroad depot located at 220 North Eleventh Street.