The East Branch and West Branch of the Conestoga join to form the main river just north of Morgantown, and the stream flows from northeast to southwest for more than 60 miles (97 km), passing close to the center of Lancaster and ending at Safe Harbor along the Susquehanna River, approximately 16 miles (26 km) north of the Pennsylvania-Maryland state line.

In the eighteenth century, British colonists in Pennsylvania called them the Conestoga, referring to the river, and to the village the Susquehannock established about 1690.

[6] An earlier Susquehannock palisaded village known as the Roberts Farm Site (36LA1) had been located nearby on a knoll above the Conestoga River and was occupied from c. 1625 to c. 1645.

[6] For several decades Conestoga Town was important fur trading center, and a meeting place for negotiations between Pennsylvania and various Indigenous groups.

The population declined due to out-migration, and the remaining Conestoga became increasing impoverished and dependent on the Pennsylvania government, who occasionally provided clothing and provisions.

Though scenic, the Conestoga River is impaired from nitrogen and phosphorus pollution, mostly runoff from animal waste and excessive commercial fertilizer.

The stream flows through a pastoral landscape farmed extensively by Pennsylvania German farmers and along the eastern and southern outskirts of the city of Lancaster.