From early colonial times, the Mid-Atlantic region was settled by a wider range of European peoples than in New England or the South. The New Netherland settlement along the Hudson River in New York and New Jersey, and for a time New Sweden along the Delaware River in Delaware, divided the two great bulwarks of English settlement from each other. The original English settlements in the region notably provided refuge to religious minorities, Maryland to Roman Catholics, and Pennsylvania to the Friends and the mostly Anabaptist Pennsylvania Germans. In time, all these settlements fell under English control, but the region continued to be a magnet for people of diverse nationalities.

Early settlers were mostly farmers and traders, and the region, called the Middle Colonies, served as a stategic bridge between North and South. Philadelphia, midway between the northern and southern colonies, was home to the Continental Congress, the convention of delegates from the original colonies that organized the American Revolution. The same city was the birthplace of the Declaration of Independence in 1776 and the U.S. Constitution in 1787.

Like New England, the Mid-Atlantic region has seen much of its heavy industry relocate elsewhere. Other industries, such as drug manufacturing and communications, have taken up the slack. Most of the nation's television stations are stationed in the Mid-Atlantic, as well as many of the insurance, medicare, and business corporations in North America.