The Merrimack River begins in the New Hampshire town of Franklin, where the Pemigewasset River (which starts in the Profile Lake in the Franconia mountains) joins the Winnipesaukee River (which flows out of Lake Winnipesaukee) to form the Merrimack.

With a total length of 110 miles, the Merrimack has a 5,000-square-mile watershed that covers much of southern New Hampshire and a portion of northeastern Massachusetts. On its banks are a number of small cities built to take advantage of water power in the 19th-century, when textile mills dominated New England economy: Concord (the state capital), Manchester, and Nashua in New Hampshire, and Lowell, Lawrence, and Haverhill in Massachusetts.

The river is best known for the early American classic of literature, "A Week on the Concord and Merrimack River" by Henry David Thoreau.

Among its tributaries is the Souhegan River, which extends west from the town of Merrimack.