Its location is 80 miles (130 km) northwest of Fort Lauderdale on the Atlantic coastal plain.

The first permanent settlement began in 1920, when John O'Brien of Philadelphia and Alonzo Clewis (1864-1944) of Tampa purchased a large tract of land to establish a town.

The US Sugar Corporation, however, remained the dominant manufacturer in Clewiston, which became known as "America's Sweetest Town".

On June 24, 2008, Governor Charlie Crist announced that the state of Florida had arranged to buy for $1.75 billion the company's 187,000 acres (76,000 ha), including the refinery in Clewiston.

On November 11, the plan was scaled back to $1.34 billion for 181,000 acres (73,000 ha) of farmland, no longer including the mill, citrus processing facilities and other assets.

It would then be converted into reservoirs and water-filtering areas as part of the ongoing restoration of the Everglades ecosystem.

Clewiston is located in the northeast corner of Hendry County at 26°45′12″N 80°56′01″W / 26.753399°N 80.933600°W / 26.753399; -80.933600,[4] on the southwestern shore of Lake Okeechobee.

Florida State Road 80 runs with US 27 through Clewiston but leads west 31 miles (50 km) to LaBelle, the Hendry County seat.

As of the 2020 United States census, there were 7,327 people, 2,532 households, and 1,921 families residing in the city.

The Clewiston Library has a Florida room to house historical reference material and books pertinent to local and state history.