Clarendon is located approximately 75 miles east of Little Rock and 80 miles southwest of West Memphis. It is located along the banks of the White River near the mouth of the Cache River. Because of its location near the two rivers, the future town site was home to European settlers before 1800.

Known as Mouth of the Cache until 1837, the town boasted a ferry and a post office by 1828 and had grown to become one of the area's important river towns as well as the crossing point of the first east-west road in Arkansas Territory. After being renamed Clarendon (many believe after the Earl of Clarendon), the town was incorporated in 1859. After being reduced to ashes by Federal forces in 1864, Clarendon rebounded and, by the beginning of the 1890s, became a cotton center and industrial port and home to the first stave and barrel factory in the state. Clarendon's Pearl Market, thought to be one of the first in Arkansas, was a huge draw for residents throughout the United States. By the end of the first decade of the 20th century, Clarendon continued to flourish and was home to more than 50 businesses and factories.

Because of the town's location near the White and Cache rivers, floods had been a continual threat to the town's residents. On April 20, 1927, the threat became reality. After months of heavy rains, the levee along the White River broke and, within 10 minutes, the entire town was flooded, as it would remain for several weeks. The town was virtually destroyed. Resilient residents refused to allow the town to die. A new levee system was completed in 1937 and has since protected the residents of Clarendon from Mother Nature's raging waters.

The city, in part due to its prime location along the White River, has watched history unfold. During the Civil War, Clarendon saw strategic troop movements, such as U.S. Generals Steele and Davidson's approaches during the Little Rock Campaign; Confederate General James Fleming Fagan's approach to Helena; and Generals Steele and Curtis's movements during the second phase of the Pea Ridge Campaign. The historic relocation movement of the southeastern Indian tribes during the Trail of Tears also moved through Clarendon. These passages, along with other historically significant routes, are now part of the Arkansas Heritage Trails System.

Thanks to its proximity to the rivers and the Big Woods of Arkansas, Clarendon is a haven for sportsmen. Hunting and fishing abound all around Clarendon, which is situated between the Cache River and White River National Wildlife Refuges. These two public areas have been named “internationally important wetlands.” The Clarendon Welcome Center, located in the restored Merchants and Planters Bank near the town square, houses displays on the history of Clarendon and Monroe County. Clarendon is on the Monroe County Loop off the Great River Road National Scenic Byway.