The river was the original source of power and commerce in the Rochester area. Many grist mills along the river grind more flour than anywhere else in North America, giving Rochester her nickname "Flour City".
The present river is the western branch of the preglacial system. Along its entire course, the rock layers are tilted to the south an average of forty feet per mile, so the river flows across progressively older bedrock as it flows northward. It rises in the highlands of the Allegheny Plateau in conglomerate, sandstone and shale rocks of Mississippian and Pennsylvanian age, passing through and often exposing older rocks as it drops. At Letchworth it exposes shales (some rich in hydrocarbons), siltstones and some limestones of Devonian age. At Rochester it again cuts a canyon with three more waterfalls in limestones and shales of Silurian age. The river is a highly favored area for fossil collectors, as one can find a great variety from a very long time span, within the short course of the river.
The falls at present day Rochester were likely the main reason for the city's existence, as they provided water power for mills. When the Erie Canal was completed in 1825 the mills could ship their products cheaply to New York City, and business boomed. Rochester became known as the Flour City.
The Erie Canal crossed the Genesee River by a stone aqueduct a few hundred feet north of the center of the then Village of Rochester. The original aqueduct was completed in September 1823 and was 802 feet long and 17 feet wide. The aqueduct was rebuilt between 1836 and 1842. This enlarged aqueduct was 848 feet long and 45 feet wide. The 1842 aqueduct can be seen today as the lower level of the Broad Street (Rochester) bridge across the Genesee River. The erie canal was rerouted south of Rochester in 1917 and now flows across the river at grade in Rochester's Genesee Valley Park.
Most of New York west of the Genesee River was part of the Holland Purchase after the American Revolution. From 1801 to 1846 the entire region was sold to individual owners from the Holland Land office in Batavia, New York. Today the region derives its name from the river and is generally referred to as Genesee Country. To the east of the river is the Finger Lakes geographic region.
Following the spectacular success of the Erie Canal, completed in 1825, a group of investors dreamed of connecting the Erie Canal to the Mississippi River System by building a new canal from the Erie, near Rochester, up the Genesee Valley, across to the Allegany River at Olean, thence downward to the Ohio and Mississippi valleys. Construction of the Genesee Valley Canal was begun in 1836, and new sections extended upriver, southward until 1880. During that time the canal was an important commercial route for the valley. The canal was plagued by frequent flood damage and the final leg down the Allegany River was never completed.
The most difficult section to build was the bypass around the gorge and falls at present day Letchworth Park. The canal followed the old Native American portage route, which necessitated many locks. These old locks can still be seen near Nunda. The project was abandoned and the right of way was sold in 1880. The property became the roadbed for the Genesee Valley Canal Railroad, which eventually merged with the Pennsylvania Railroad. Much of the canal and railroad right-of-way is open to the public today as the Genesee Valley Greenway.
On Friday, November 13, 1829 (Friday the 13th), Sam Patch, the daredevil, jumped to his death before 8,000 spectators at the Upper Falls of the Genesee in Rochester.
In 1865, a sudden march thaw flooded Downtown Rochester, the worst flood in the City's history. After a flood in 1913 that was almost as severe, the rock bed of the Genesee River in Downtown Rochester was cut to make the river channel deeper.
In 1852 a wooden railroad bridge was built over the Upper Falls at Portageville. It was the largest of all wooden bridges built at the time. The wood from 300 acres (1.2 km²) of trees was required for its timber.
The "great flood of 1972", spawned from the remnants of Hurricane Agnes, wreaked devastation upon the county with the most concentrated damage occurring at and near the Village of Wellsville. Wellsville is the largest village in Allegany County, New York, which contains no cities, and is the junction of many foothill streams including Dyke Creek feeding the Genesee River from the east and Andover. Since Dyke Creek had also exceeded its bank capacity, it aided in producing a rapid and huge pool of water at the center of the Village of Wellsville. The damage area continued downstream through Scio and Amity until the valley widened to accept the large flow of water in the lesser populated area. Erosion of topsoil during this flood reduced the agricultural capacity of the county with serious consequence which eliminated many small farmers immediately.