While the railroad industry has been less prevalent since the closures and mergers of the 1950s–1960s, a wide-ranging rail transportation infrastructure still operates along the river's shores.

After meandering westwards, it turns south crossing the line again through the twin towns of Waverly, New York, and Sayre, Pennsylvania, and their large right bank railyard, once briefly holding the largest structure in the United States devoted to the maintenance and construction of railroad locomotives.

It receives the Lackawanna River southwest of Scranton and turns sharply to the southwest, flowing through the former anthracite industrial heartland in the mountain ridges of northeastern Pennsylvania, past Pittston City (Greater Pittston), Wilkes-Barre, Nanticoke, Shickshinny, Berwick, Bloomsburg, and Danville, before receiving the West Branch at Northumberland.

At Jersey Shore, Pennsylvania, Pine Creek, the largest tributary of the West Branch Susquehanna River, is received.

Harrisburg is the largest city located on the lower river, which flows southeast across South Central Pennsylvania, forming the border between York and Lancaster counties, and receiving Swatara Creek from the northeast.

[19] The Lenape are an Algonquian-speaking Native American people who had communities ranging from coastal Connecticut through New York and Long Island, and further south into New Jersey and Delaware in the mid-Atlantic area.

[22] In addition, John Smith of Jamestown, Virginia, labeled their settlement as "Sasquesahanough" on his 1612 map when he explored the upper Chesapeake Bay area.

[23] In Virginia and other southern colonies, Siouan-speaking tribes constituted a third major language family, with their peoples occupying much of the middle areas of the interior.

In late colonial times, the river became an increasingly important transportation corridor, used to ship anthracite coal, discovered by Necho Allen, from its upper reaches in the mountains to the markets downriver.

Together on August 29, they defeated the Tories and warriors of allied Iroquois bands at the Battle of Newtown (near present-day Elmira, New York).

Following the United States gaining independence in the Revolutionary War, in 1790 Colonel Timothy Matlack, Samuel Maclay and John Adlum were commissioned by the Supreme Executive Council of the Commonwealth of Pennsylvania to survey the headwaters of the Susquehanna river.

[25] In 1792, the Union Canal was proposed in order to link the Susquehanna and the Delaware rivers in Pennsylvania along Swatara and Tulpehocken creeks.

In the 19th century, many industrial centers developed along the Susquehanna, using its water power to drive mills and coal machinery, to cool machines, and as a waterway for the transport of raw and manufactured goods.

[26] Boats had to climb a net height of 1,009 feet (308 m) between basins, requiring the use of more than 100 water locks, which were too expensive to be maintained under the new competition.

It holds that Joseph Smith and Oliver Cowdery received the priesthood from heavenly beings at a site along the Susquehanna and performed their first baptisms of Latter Day Saints in the North Branch of the river.

He positioned militia units under Maj. Granville Haller to protect key bridges in Harrisburg and Wrightsville, as well as nearby fords.

[27] In 1972 the remnants of Hurricane Agnes stalled over the New York-Pennsylvania border, dropping as much as 20 inches (510 mm) of rain on the hilly lands.

The Chesapeake Bay received so much fresh water that it altered the ecosystem, killing much of the marine life that depended on saltwater.

The worst affected area was Binghamton, New York, where record-setting flood levels forced the evacuation of thousands of residents.

In September 2011 the Susquehanna River and its communities were hit by Tropical Storm Lee, which caused the worst flooding since Agnes in 1972.

Before the Port Deposit Bridge opened in 1818, the river formed a barrier between the northern and southern states, as it could be crossed only by ferry.

Many canal remnants can be seen; for example, in Havre de Grace, Maryland, along US Route 15 in Pennsylvania, and in upstate New York at various locations.

[35] The designation provides for technical assistance from federal agencies to state and local governments working in the Susquehanna watershed.

During this study, various series of gamma-emitting radionuclide concentration measurements were made in many general categories of animals, plants, and other inorganic matter, both within and near the river.

In May 1986, ongoing measurements from several monitoring stations along the river near Three Mile Island, Peach Bottom and Calvert Cliffs detected iodine-131 beta particles attributable to fallout from the Chernobyl nuclear accident.

[39] In 2015, a smallmouth bass with a rare, cancerous tumor was caught from the river, raising renewed concerns about toxic materials and water pollution.

[40][41] The Environmental Protection Agency reported, "we do not have sufficient data at this time to scientifically support listing the main stem of the Susquehanna as impaired.

The General Clinton Canoe Regatta, a 70-mile (110 km) flat-water race, takes place each year in Bainbridge, New York, on Memorial Day weekend.

Binghamton University Crew and Hiawatha Island Boat Club are also located on the river, in the Southern Tier of New York.