This, combined with increased pressures from land use change for urban development, means the river has been suffering significant stress.

[4] These dams and weirs have had a potent effect, blocking migratory native fish like Australian bass (also locally commonly known as perch) from much of their former habitat, and reducing floods and freshets needed for spawning.

At Emu Plains, the western bank of the river provides a location for outdoor theatre productions on warm summer nights.

The eastern bank at Penrith provides barbecue facilities and children's play equipment, as well as a wide pathway running for several kilometres for strolls along the riverbank.

Near Penrith, since 1971 numerous Aboriginal stone tools were found in Cranebrook Terraces gravel sediments deposited by the Nepean River 40,000 to 50,000 years ago, according to repeated, revised and corroborated radiocarbon and thermoluminescence dating.

Karskens et al. have made an attempt to recover, integrate and map archaeological data of the area from both published and unpublished reports.

[12] Phillip named the river after Lord Hawkesbury, later titled Charles Jenkinson, 1st Earl of Liverpool, President of the Privy Council Standing Committee on Trade.

[14] During the 1820s, the Nepean district's most famous early settler, the landowner and physician Sir John Jamison (1776–1844), erected a Georgian mansion, called Regentville House, on the model estate which he had established on a rise overlooking the river, not far from the present-day city of Penrith.

Despite forming the effective western and south-western boundary of the metropolitan region of Sydney for its entire length, there are very few fixed crossings of the Nepean River.

[20] During the 2021 New South Wales floods, the Nepean River became overflowed, peaking at 10 m (32.81 ft), with Windsor Bridge submerging in its waters, leading to inundated homes and isolated animals in the surrounds.

[21] The Australian Mandaean community in the Sydney metropolitan area regularly performs masbuta (baptism) rituals in the Nepean River,[22] typically in and around Wallacia Mandi.