At the beginning of the 17th century, Connecticut was the home of a number of different Native American groups, all of whom spoke related Algonquian languages. Archaeological sites indicate these people lived largely by hunting deer, catching fish and shellfish, and growing corn, beans, and squash. They migrated from forest to coastal areas to take advantage of seasonal resources. The total native population is estimated at about 7,000 people in the early 1600s, after an epidemic that decimated Native Americans throughout New England.

Most powerful among the Connecticut people were the Pequot, who lived in the east and along the shore of Long Island Sound, an area they had conquered from other native groups at the end of the 1500s. Early in the 1600s, a number of Pequot split off from the main group. Led by a chief named Uncas, they called themselves Mohegan, and controlled an area near the Thames River .

Other native groups were the Nipmuc in the northeastern sections of Connecticut; the Niantic along the eastern coast; and the Hammonasset, Quinnipiac, Paugussett, Siwanoy, Podunk, Poquonnuc, Massacoe, and Tunxis in the central and western sections.

Most of the Native Americans were generally friendly to the colonists. Some native groups invited the English to settle nearby, hoping for trade and for allies against the aggressive Pequots, who dominated the area. Settlers purchased land from the native people, and though whites often encroached on native territory, disputes were usually settled without violence. The exception to these friendly relations was friction between the Pequots and settlers, which soon escalated into New England's first major war, the Pequot War of 1637.