Downstream from the confluence of its branches it flows south past Selinsgrove, where it is joined by its Penns Creek tributary, and cuts through a water gap at the western end of Mahantongo Mountain. It receives the Juniata River from the northwest at Duncannon, then passes through its last water gap, through Blue Mountain Pennsylvania, just northwest of Harrisburg. It passes downtown Harrisburg (where it is nearly a mile wide), the largest city on the lower river, and flows southeast across South Central Pennsylvania, forming the border between York and Lancaster counties, as well as receiving Swatara Creek from the northeast. It crosses into northern Maryland approximately 30 miles (50 km) northeast of Baltimore, where it is joined by Octoraro Creek. Finally the river enters the northern end of the Chesapeake Bay at Havre de Grace, where Concord Point Light was built in 1827 to accommodate the increasing navigational traffic.
Before the end of the last ice age, the Susquehanna was a much longer river. The Chesapeake Bay constituted its lower valley before it was flooded by rising waters at the conclusion of the Pleistocene, a formation known as a ria.
The environmental group American Rivers named the Susquehanna "America's Most Endangered River for 2005" due to the excessive pollution it receives. It is the habitat of the Pennsylvania wood cockroach. Most of the pollution in the river is due to excess animal manure, agricultural runoff, urban and suburban stormwater, and raw or inadequately treated sewage. In 2003 the river alone contributed 44% of the nitrogen, 21% of the phosphorus, and 21% of the sediment flowing into the Chesapeake Bay. Pennsylvania may be subject to EPA sanctions if it does not reduce its pollution in the watershed by 2010. It was designated as one of the American Heritage Rivers in 1997.
In the late colonial times, the river became an increasingly important transportation corridor with the discovery of anthracite coal by Necho Allen in its upper reaches in the mountains. In 1792, the Union Canal was proposed linking the Susquehanna and the Delaware along Swatara Creek and Tulpehocken Creek. In the 19th century, the river became the scene of the growth of industrial centers.
In 1779 General James Clinton led an expedition down the Susquehanna after making the upper portion navigable by damming up the river's source at Otsego Lake, allowing the lake's level to rise, and then destroying the dam and flooding the river for miles downstream. This event is described by James Fenimore Cooper in the introduction to his popular novel The Pioneers. At Athens, Pennsylvania, then known as Tioga or "Tioga Point", Clinton met up with General John Sullivan's forces, who had marched from Easton, Pennsylvania. Together on August 29, they defeated the Tories and Indians at the Battle of Newtown (near today's city of Elmira, New York). This became known as the "Sullivan-Clinton Campaign" or the "Sullivan Expedition."
Conflicting land claims by Pennsylvania and Connecticut to the Wyoming Valley along the Susquehanna led to the founding of Westmoreland County, Connecticut, and the Pennamite Wars, which eventually led to the territory being ceded to Pennsylvania.
The Susquehanna River holds importance for members of The Church of Jesus Christ of Latter-day Saints as the location where Joseph Smith, Jr. and Oliver Cowdery received the priesthood from heavenly beings. On 15 May, 1829, according to section 13 of the Doctrine and Covenants, they were visited by the resurrected John the Baptist. Following his visit, Joseph and Oliver baptized each other in the river. Later that year, they were also visited near the river by the apostles Peter, James and John, as alluded to in sections 27 and 128 of the Doctrine and Covenants. Both events took place in unspecified locations near the river's shore in either Susquehanna County, or Broome County.
During the American Civil War's 1863 Gettysburg Campaign, the commander of the Department of the Susquehanna, Union Major General Darius N. Couch resolved that Robert E. Lee's Confederate Army of Northern Virginia would not cross the Susquehanna. He positioned militia units under Maj. Granville Haller to protect key bridges in Harrisburg and Wrightsville, as well as nearby fords. Confederate forces approached the river at several locations in Cumberland and York counties, but were recalled on June 29 when Lee chose to concentrate his army to the west.
In 1972, the remnants of Hurricane Agnes stalled over the New York-Pennsylvania border, dropping as much as 20 inches (50.8 cm) of rain on the hilly lands. Much of that precipitation was received into the Susquehanna from its western tributaries, and the valley suffered disastrous flooding. Wilkes-Barre, Pennsylvania, was among the hardest hit communities. The Chesapeake Bay received so much fresh water that it killed much of the marine life.
In June 2006, significant portions of the river system were affected by the Mid-Atlantic Flood of June 2006, a flood caused by a stalled jet stream-driven storm system. The most significantly affected area in the Susquehanna river basin was in and around the Binghamton, NY region, where flooding exceeded historical records and forced the evacuation of thousands of residents and the destruction of significant amounts of property and infrastructure.
The Susquehanna River has always loomed large in the transportation history of the United States. Prior to the 1818 opening of the Port Deposit Bridge, the river formed a barrier between the northern and southern states, crossable only by ferry. The earliest dams were constructed to support ferry operations in low water. The presence of many rapids in the river meant that while commercial traffic could navigate down the river in the spring thaws, nothing could move up. This led to the construction of two different canal systems on the lower Susquehanna; the first was the Susquehanna Canal, also called the Conowingo Canal or the Port Deposit Canal, completed in 1802 by a Maryland company known as the Proprietors of the Susquehanna Canal; the second was the much longer and more successful Susquehanna and Tidewater Canal. The canals required additional dams to provide canal water and navigation pools. As the industrial age progressed, bridges replaced ferries, and railroads replaced canals, often built right on top of the canal right of way along the river. Many canal remnants can be seen in Havre de Grace, Maryland, along US Route 15 in Pennsylvania, and in upstate New York at various locations. These latter remnants are parts of the upstream divisions of the Pennsylvania Canal, of privately funded canals, and of canals in the New York system. Today, there are over two hundred bridges crossing the Susquehanna. The sole remaining ferry, at Millersburg, Pennsylvania, is a seasonal tourist attraction. The canals are gone or are part of historical parks, and dams are related to power generation or recreation. Perhaps the most famous of the bridges, the Rockville Bridge, crosses the river from Harrisburg, Pennsylvania, to Marysville, Pennsylvania. The Rockville Bridge, when constructed, was the longest stone masonry arch bridge in the world. It was built by the Pennsylvania Railroad in the early 1900s, replacing an earlier iron bridge.