The area was originally inhabited by the Ais tribe, a hunter-gatherer culture whose territory extended from south of the St. John's river to the St. Lucie Inlet.

During the early 19th century, the Spanish government issued several land grants in the area, one of which went to settler James Hutchinson.

In 1841, the United States government began issuing land grants under the Armed Occupation Act to Americans who were willing to settle the area.

Major industries at the end of the 19th century in the area included pineapple, fishing and seafood canning and cattle.

The 1920s saw increased land speculation and planned developments such as Indrio and San Lucie that never came to fruition due to the bust in 1929.

During World War II the United States Naval Amphibious Training Base was established in Fort Pierce on North and South Hutchinson Island.

The post-war years saw a major population boom in the area, some of which were returning sailors and their families that had undergone training at the Navy base.

[3] In 1958, the General Development Corporation, a subsidiary of Mackle Brothers, bought tens of thousands of acres of land along the St. Lucie River in the southern part of the county in order to build a new community.

Colorful and clever advertising soon drew thousands of northeastern retirees and families to the area, laying the foundation for the future city of Port St. Lucie.

The early 21st century brought many trials for the county including two major hurricanes in 2004 and an economic and housing slump starting in 2008.

On June 3, 2002, the Florida Department of Transportation (FDOT) approved funding, expanding the bus service to Martin County, and became the Treasure Coast Connector.

[7][8] Until 1968 the Florida East Coast Railway operated Jacksonville to Miami service, with station stops in Fort Pierce and Jensen Beach.

Until 1963 long distances passenger trains of the Illinois Central (City of Miami) and Louisville and Nashville (Dixie Flagler and South Wind) from Chicago and Atlantic Coast Line from New York City (East Coast Champion, the Havana Special, and the winter-only Florida Special) made stops in Fort Pierce.

[9][10] In 2023, Brightline, an inter-city rail route that currently runs between Miami and Orlando, announced that it was looking for sites for a new station on the Treasure Coast.

[12][13] [19] The 2020 United States census counted 329,226 people, 128,997 households, and 88,835 families in St. Lucie County, Florida.

[25] The 2016-2020 5-year American Community Survey estimates show that the median household income was $55,237 (with a margin of error of +/- $1,568).

[36] According to census[37] of 2000, the largest ancestry groups in St. Lucie County were: English 34%, African 15%, Irish 14%, German 13%, Italian 10%.