Once home to a variety of industries, today Clarendon's economy is largely based on agriculture.

Similar to many Delta communities, the city's population has been dwindling since mechanization on the farm reduced the number of agricultural-related jobs in the area.

By 1799, French hunters and trappers had built cabins at the mouth of the Cache River.

It was the point where the Military Road from Memphis, Tennessee, to Little Rock crossed the White River.

By that date, a ferry crossing and post office had been established in Clarendon, and the town served as the terminus for a stagecoach line to the west.

The Military Road was used as the route for some groups of Native Americans being relocated from eastern states to Oklahoma during the forced relocations commonly known as the Trail of Tears; Chickasaw, Choctaw, Creek, and Cherokee groups are known to have traveled along it.

In 1864, the city was burned to the ground by Union forces in retaliation for the sinking of the tinclad Union gunboat USS Queen City by forces under the command of Confederate Brigadier General Joseph O. Shelby.

In the early 1900s, Clarendon developed a number of industries, including lumber, staves and barrels, oars, and buttons made from the shells of the area's plentiful freshwater mussels.

[10] The climate in this area is characterized by hot, humid summers and generally mild to cool winters.

As of the 2020 United States Census, there were 1,526 people, 741 households, and 397 families residing in the city.

A total of 3,318 patients utilized the clinic in 2013 according to the Bureau of Primary Health Care.

The 1931 bridge, listed on the National Register of Historic Places (NRHP) and Historic American Engineering Record (HAER),[16] has been subject to local restoration efforts as a bike and pedestrian path.

The facility uses a lagoon system, filters, and chlorination to produce treated effluent in accordance with the city's NPDES permit administrated by the Arkansas Department of Environmental Quality (ADEQ).