The cities of Rockland, Belfast, Brewer and Bangor, and the towns of Rockport, Camden, Northport, Searsport, Stockton Springs, Castine, Bucksport, Frankfort, Winterport, Orrington, and Hampden developed adjacent to the Penobscot River estuary.

The river upstream of Bangor became an important transportation corridor for log driving to bring wooden logs and pulpwood from interior forests to sawmills and paper mills built to use water power where the city of Howland and the towns of Veazie, Orono, Old Town, Milford, Passadumkeag, West Enfield, Lincoln, Winn, Mattawamkeag, Medway, and Millinocket developed.

During Father Rale's War, New England settlers from Massachusetts also sent periodic raiding parties to the Penobscot, destroying the primary native village in 1723.

[citation needed] The first permanent settler from British North America on the river was Joshua Treat (1726–1802), who was initially the armorer and translator at Fort Pownall.

His oldest son, Joshua Treat, Jr., built a log house and sawmill at Marsh Bay in what is now Frankfort, and other members of their extended family, joined by additional settlers from Massachusetts and New Hampshire, pushed ever further up-river, eventually restricting the Penobscot people to Indian Island (Old Town, Maine), the present Penobscot Indian Reservation.

During the War of 1812, the British again invaded Maine and defeated an American force at the Battle of Hampden, sacking the town of Bangor in the process.

In 1931 the Waldo-Hancock Bridge was opened to carry US Route 1 across the river at the Penobscot Narrows between Prospect, in Waldo County, and Verona Island just below Bucksport.

Dioxins, which are highly potent toxic chemicals that may cause cancer and other health problems, were being poured daily into this adjacent river, the Penobscot.

"[7] As an Indigenous community trying to maintain traditional subsistence living and eating such as fishing or foraging, their way of life and their physical bodies are unequally burdened by issues of water quality and pollution.

The 2015 collaborative report, The Penobscot River and Environmental Contaminants: Assessment of Tribal Exposure Through Sustenance Lifeways, confirms through a four-year quantitative study that these unequal burdens and harmful level of toxins are very real threats and realities faced by the community's indigenous people.

[9] Sockbeson concludes that a treaty is required to ensure that "the breast and spoon we feed our babies with is not filled with cancer, diabetes, learning disabilities, and attention deficit [disorder].

Due to the pollution of the Penobscot river, the waterways, plants, and environment which the nation relies on for their way of life have become contaminated.

June Sapiel, an activist and member of the Penobscot Nation, is quoted describing the importance of the river, saying "Our water is sacred.

[citation needed] In the 21st century, with the continuing decline of the Maine paper industry, and the divestiture of its woodlands, the Penobscot watershed has become more and more associated with recreational use (fishing, hunting, boating, and tourism) and less with manufacturing.

On October 7th, 2020, it was discovered that the Nine Dragons (ND) Paper Mill in Old Town, Maine had spilled chemicals into the Penobscot River.

ND Paper Mill reported the spill to the Department of Environmental Protection who assisted in cleanup and repairs to the damaged sewer line.

The spill created a large plume of foam and smoke, and local residents reported a strong chemical odor in the air.

[26] In response to the issue, ND Paper replaced multiple failed floor drains and about 400 feet of steel piping for the sewer system.

[28] While ND Paper has taken steps to improve its environmental performance since the spill, concerns remain about its impact on the environment and the local community.

The chemicals released in the spill can cause significant harm to aquatic life, and can also contaminate drinking water supplies.

The lasting effects that this spill has had on the Penobscot Nation has caused them to lose one of their main food sources, as it has been recommended that less fish be consumed from the river.

The introduction of mercury into the Penobscot River is extremely dangerous and was described as "imminent and substantial endangerment to public health and the environment," as this watershed is a main source of shellfish and fish alike.

A court ordered study was completed by the company Mallinckrodt, which over the course of nine years found that the Penobscot River had levels of mercury which were up to 20 times higher than the surrounding areas.

[31] Because of these extremely high levels of mercury which were discovered, the Agency for Toxic Substances and Disease Registry (ATSDR), recommend that members of the Penobscot Indian Nation, (PIN), limit consumption of fish and snapping turtles caught in the river to 1-2 meals per month.

When I was a child, the river was thick with foam, had an odor at all times, and if you swam in it, your clothing would be stained and skin would break out.

And our history, traditions, and cultural identity are very much intertwined with it,"[37] In 2021, a cleanup plan was set into place 22 years after a lawsuit was filed against Mallinckrodt US LLC.

This cleanup plan consists of long term monitoring as well as cleaning up the area, along with providing funding to projects for communities and environments which have been affected by this pollution.