From Pawtucket Falls in Lowell, Massachusetts, onward, the Massachusetts–New Hampshire border is roughly calculated as the line three miles north of the river.

In 1604 the natives of later New England told Pierre Dugua, Sieur de Monts, who was leading a colony of French language speakers to Acadia (later Nova Scotia), of a beautiful river to the south.

According to Joseph B. Walker,[4][full citation needed] relying on Chandler Eastman Potter's The History of Manchester (1856), Merremack contains the elements merruh ("strong") and auke ("place"—a recognizable locative ending), and means "the place of strong current,- a term not inappropriate, when we consider ... the river's rapids ...." Potter was an authority on Native American affairs in colonial New England.

Upon the glacier's retreat, debris deposited north of Boston filled the lower Merrimack Valley, redirecting the river into its current northeast bend at Lowell.

On the Merrimack River's banks are a number of cities built to take advantage of water power in the 19th century, when textile mills dominated the New England economy: Concord, Manchester, and Nashua in New Hampshire, and Lowell, Lawrence, and Haverhill in Massachusetts.

Prior to the construction of the Middlesex Canal, Newburyport was an important shipbuilding city, in a location to receive New Hampshire timber that had been floated downriver.

From there, the river flows south through Concord, Manchester, and Nashua, entering Massachusetts at the town of Tyngsborough, where it turns northeast and winds past or through Chelmsford, Lowell, Dracut, Tewksbury, Andover, Methuen, Lawrence, North Andover, Haverhill, Groveland, West Newbury, Merrimac, and Amesbury, to its mouth at the Gulf of Maine between the city of Newburyport and the town of Salisbury.

Citizens recall that the river had unusual colors, smells, and vegetation as a result of the pollution from textile mills and other human-related waste.

[12] In the 1960s, the Merrimack River was one of the ten most polluted waterways in the United States due to years of unmediated dumping of raw sewage, paper and textile mill discharge, and tannery sludge.

[13] Phthalates, a group of chemicals used in the manufacture of plastics and detrimental to human bodily systems, were identified in high concentrations within the river in 1973.

In addition, human recreational activities such as swimming and boating have been restricted in certain areas of the river due to high contamination levels.

Birds, fish, and other animals returned to inhabit the river, with citizens noting specifically seeing much more American shad, striped bass, trout, and Atlantic salmon.

Additionally, the use of road salt in the winter has remained a major pollutant since the 1970s, and chloride contamination in the Merrimack River continues to impact aquatic life.

The song "Merrimack River" and its instrumental reprise are featured on the 2009 album Amanda Leigh by Nashua, New Hampshire, native Mandy Moore.

Anya Seton's historical novel Avalon includes a section depicting the fictional Pre-Columbian arrival of 9th century Irish and English travelers at the Merrimack River and their interactions with local Native Americans.