Amesbury is located at 42°51′29″N 70°55′50″W. According to the United States Census Bureau, the city has a total area of 13.6 square miles, of which, 12.4 square miles of it is land and 1.2 square miles of it (9.08%) is water. Amesbury is drained by the Powow River.

Powow Hill, elevation 332 feet, is the highest point in town. Once the site of Indian gatherings, or "powows," it has views to Maine and Cape Ann. Amesbury is the second northern-most town in Massachusetts, its northernmost point coming just south of the northernmost point of the state, in Salisbury. Amesbury lies along the northern banks of the Merrimack River, and is bordered by Salisbury to the east, Newburyport to the southeast, West Newbury to the southwest, Merrimac to the west, a small portion of Newton, New Hampshire to the northwest, and South Hampton, New Hampshire to the north.