The word "Conococheague" is translated from the Delaware Indian or Unami-Lenapi term òk'chaxk'hanna, which means "many-turns-river.
The creek flows southwest, turning west at Caledonia State Park, and continues past Fayetteville into the Great Appalachian Valley, turning southwest at Chambersburg and flowing west of Greencastle.
Over the past 30 years there has been a steady decline in the number of available native fish species, such as yellow perch, eel, horned chub, calico bass, rock bass, and white sucker, and overall water quality due to sediment collection on the bottom, thereby severely limiting the ability of these native species to spawn.
This in turn has made parts of the lower East Branch ideal for catching huge crayfish at night; however, the food value of this species, due to pollution, is dubious at best.
The West Branch flows southwest along the Tuscarora Trail to around Fort Loudon, then turns south, and finally southeast, joining the main stem 8.2 kilometres (5.1 mi) north of the Mason–Dixon line.