Plymouth was the site of the second colony in New England after Popham Colony in 1607 in what is now Maine. Plymouth was founded in 1620 by the Pilgrims, passengers of the Mayflower. In 1692, the town of Salem and surrounding areas experienced one of America's most infamous cases of mass hysteria, the Salem witch trials. In 1777, General Henry Knox founded the Springfield Armory, which during the Industrial Revolution catalyzed numerous important technological advances, including interchangeable parts. In 1786, Shays' Rebellion, a populist revolt led by disaffected American Revolutionary War veterans, influenced the United States Constitutional Convention. In the 18th century, the Protestant First Great Awakening, which swept the Atlantic World, originated from the pulpit of Northampton preacher Jonathan Edwards. In the late 18th century, Boston became known as the "Cradle of Liberty" for the agitation there that led to the American Revolution.

The entire Commonwealth of Massachusetts has played a powerful commercial and cultural role in the history of the United States. Before the American Civil War, Massachusetts was a center for the abolitionist, temperance, and transcendentalist movements. In the late 19th century, the sports of basketball and volleyball were invented in the western Massachusetts cities of Springfield and Holyoke, respectively. In 2004, Massachusetts became the first U.S. state to legally recognize same-sex marriage as a result of the decision in Goodridge v. Department of Public Health by the Massachusetts Supreme Judicial Court. Many prominent American political dynasties have hailed from the state, including the Adams and Kennedy families. Harvard University in Cambridge is the oldest institution of higher learning in the United States,[58] with the largest financial endowment of any university, and Harvard Law School has educated a contemporaneous majority of Justices of the Supreme Court of the United States.[60] Kendall Square in Cambridge has been called "the most innovative square mile on the planet", in reference to the high concentration of entrepreneurial start-ups and quality of innovation which have emerged in the vicinity of the square since 2010. Both Harvard University and the Massachusetts Institute of Technology, also in Cambridge, have been ranked among the most highly regarded academic institutions in the world. Massachusetts' public-school students place among the top tier in the world in academic performance, and the state has been ranked as one of the top states in the United States for citizens to live in, as well as one of the most expensive.