The Chisca were a tribe of Native Americans living in present-day eastern Tennessee and southwestern Virginia in the 16th century. Their descendants, the Yuchi lived in present-day Alabama, Georgia, and Florida in the 17th, 18th, and early 19th centuries, and were removed to Indian Territory in the 1830s.

The Hernando de Soto expedition heard of, and may have had brief contact with, the Chisca in 1540. The Juan Pardo expeditions of 1566 and 1568 encountered the Chisca and fought them.

By early in the 17th century, Chisca people were present in several parts of Spanish Florida, engaged at various times and places in alternately friendly or hostile relations with the Spanish and the peoples of the Spanish mission system. After the capture of a fortified Chisca town by the Spanish and Apalachee in 1677, some Chisca took refuge in northern Tennessee, where they were absorbed into the Shawnee, and in Muscogee towns in Alabama. Around the turn of the 18th century some Chisca, by then generally called Yuchi, joined the Apalachicola Province towns that resettled around Ochisi Creek in central Georgia, thus becoming part of the "Lower Towns of the Muscogee Confederacy". A few Chiscas remained in western Florida into the middle of the 18th century.

In 1540, the Hernando de Soto expedition entered the southern Appalachian Mountains in North Carolina. At the town of Coste at the mouth of the Little Tennessee River, de Soto was told of the "Chisca" province that was north of Coste and produced copper and "another finer but softer metal of the same color". According to de Sotos's account, he sent out a small exploration party near the Nolichucky River in the vicinity of the upper Tennessee River, where they were attacked and defeated by Chisca warriors.

The Spanish established the first capital of Spanish Florida at Santa Elena, on Parris Island, South Carolina. In late 1566, Captain Juan Pardo departed from Santa Elena to explore the interior of what is now the Southeastern United States. Pardo's expedition reached Joara (at a site about 20 miles east of Marion, North Carolina) in late January 1567, where they built Fort San Juan. Pardo left Sergeant Hernando Moyana in charge of the fort when he continued his journey of exploration before returning to Santa Elena. In March of that year, Moyana reported to Pardo that he had fought a chief named Chisca, killing 1,000 Chiscas and burning 50 houses. Shortly afterwards, Moyana was challenged by another chief (assumed to also be a Chisca by Hudson, et al.). In response, Moyana marched for four days with 19 Spanish soldiers and an unspecified number of Joaras, and captured a palisaded town, killing a claimed 1,500 inhabitants and burning the town. Moyana then marched another four days to Chiaha. Chiaha was also surrounded by a palisade, and Moyana settled for building a small fort nearby. The towns destroyed by Pardo and his soldiers are identified in Spanish sources as Maniatique and Guapere. Luisa Mendez, a Native American woman who was married to a Spanish soldier, was identified as the "cacica" (female chief) of the town of Guanaytique or Manaytique. Mendez's description of brine springs in the area has been taken as evidence that Maniatique was near Saltville, Virginia on the Holston River. On the other hand, DePratter, et al. place the Chisca towns on the upper Nolichucky River or the Watauga River, or both.

People that the Spanish called Chisca were in the western part of what is now the state of Florida by late in the 16th century. A Chacato chief, Juan de Diocsale, who had a Chisca mother, was born by 1595. (Chacato Province was roughly coterminous with the Chipola River basin in what is now Jackson County, Florida.)

By the 1620s, Spanish records indicated that many Chiscas were living in the area. When Juan de Salinas was governor of Spanish Florida between 1618 and 1624, he sent soldiers 60 leagues to punish Chiscas and Chichimecos for robbing and killing Christian natives in Timucua and Apalachee provinces. In 1639, the Spanish unsuccessfully invited some Chiscas to settle near a Timucuan mission 10 leagues from St. Augustine, in hopes of using them to hunt fugitives from missions and defend the Florida colony. The Chisca roamed freely throughout Spanish Florida in the 1640s. In 1647, Chiscas were involved in the Apalachee Rebellion. After the Spanish suppressed the rebellion, Chiscas ambushed Spanish soldiers and Christian natives in neighboring Yustaga Province. The Spanish then ordered Chiscas, including some that had reached the St. Johns River valley, to settle in towns under Christian caciques, but the Chiscas remained "rebellious" in 1650 and 1651, killing some mission inhabitants, and kidnapping others. The Chisca had several settlements near the St. Johns River, from which they raided Timucua missions and the La Chua ranch. In 1651, the Spanish succeeded in driving the Chisca out of Timucua province.

Some Chisca had settled at the mouth of the Apalachicola River, near Apalachee Province, as early as 1661, and relations with the Spanish were friendly enough that they tried to recruit some Chiscas to serve as interpreters for questioning some Chichimecos held prisoner by the Spanish, and, in 1675, asked the Chiscas to not support the Chacatos in their dispute with the Spanish. In 1675, the Chisca living near Apalachee Province warned the Spanish that the English were urging the Chichimeco to attack Spanish missions and other native groups that had submitted to the Spanish king. On the other hand, that same year Pablo de Hita Salazar, governor of Florida, described the Chisca as "our enemies, rebellious people, untamed and brought up licentiously". Diaz Vara Calderon, Bishop of Cuba, described the Chisca as living "without any fixed settlements, and sustaining themselves with the hunt, nuts, and roots of trees". Calderon gave the Chisca population as more than 4,000.