Conococheague Creek, a tributary of the Potomac River, is a free-flowing stream that originates in Pennsylvania and empties into the Potomac River near Williamsport, Maryland. It is in length, with in Pennsylvania and in Maryland. The watershed of Conococheague Creek has an area of approximately, out of which only are in Maryland. The word "Conococheague" is translated from the Delaware Indian or Unami-Lenapi term òk'chaxk'hanna, which means "many-turns-river." The Conococheague, or Connogochegue, as it was known at the time, was the northernmost extent of the range along the Potomac within which Congress in the Residence Bill of 1790 authorized the establishment of the Federal District, known as the District of Columbia. By presidential proclamation, George Washington placed the District at the lower end of the range, near the "Eastern Branch", later Anacostia River, which marked the southernmost extent of the Residence Bill's range. The water divide between Conococheague Creek and Conodoguinet Creek is sometimes used as the boundary between the Hagerstown Valley and the Cumberland Valley.
Conococheague Creek, above its confluence with its West Branch, is sometimes referred to as the East Branch Conococheague Creek. At, the "East Branch" is shorter than the West Branch. It rises in the South Mountain range of south-central Pennsylvania, forming in northwestern Adams County between East Big Flat Ridge and Piney Mountain. 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. The creek from Fayetteville to its confluence with Back Creek near Williamson is very polluted from farm runoff. 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.
Conococheague Creek continues south into Maryland and enters the Potomac near Williamsport, where the Great Philadelphia Wagon Road crossed the river at William's Ferry, continuing on to Winchester, Virginia. The crossing is where Braddock's forces crossed the Potomac after leaving Frederick on their way to Winchester. The Tuscarora Trail crosses the Conococheague.