The Agawam tribe inhabited Topsfield prior to and during the British colonization in the early seventeenth century. They were one of the Algonquian peoples. They claimed the land north of the Danvers River, the whole of Cape Ann and from there to the Merrimack River. However, the first European explorers had brought smallpox to New England, decimating all the shore tribes from the Penobscot River to Narragansett Bay in 1616.

Chief Masconomet, for whom Masconomet Regional High School is named, was the sagamore or chief of the Agawam at this time. He welcomed Massachusetts Bay Colony Governor John Winthrop on his arrival in Salem Harbor in 1630. Masconomet deeded all the Agawams' land to Winthrop in 1638 in exchange for twenty pounds sterling. The English had settled within the bounds of modern-day Topsfield by 1643. They originally named their settlement New Meadows. Tradition has long held that the Agawam called the place Shenewemedy, meaning "the pleasant place by the flowing waters." More recent historians believe that Shenewemedy was how the Agawam pronounced New Meadows, rather than a word in their own language.

The General Court of Massachusetts renamed the place Topsfield in 1648, undoubtedly after Toppesfield, England, a small parish in the county of Essex north of London. Topsfield was incorporated as a town in 1650. Masconomet died in 1658 and was buried on Sagamore Hill, now in Hamilton. Nine years later, two young men were punished for digging up the grave of the sagamore and carrying his skull on a pole. Native Americans were held in low regard and were poorly treated by the colonists. There is no record of hostilities between the colonists and Native Americans in Topsfield, however, even during the French and Indian Wars, which covered the period 1689-97. The Topsfield town records last mention Native American residents in 1750.

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