- English expeditions by Bartholomew Gosnold (1572–1607) and Martin Pring (1580–1646) to Maine coast
- Samuel de Champlain (1567–1635) charts Maine coast; Sieur de Monts tries to establish permanent settlement on St. Croix Island
- George Waymouth (ca. 1585–ca. 1612) explores mouth of Kennebec River, captures five Indians, takes them to England
- George Popham (ca. 1550–1608) and Raleigh Gilbert (ca. 1583–1634) establish English settlement, Fort Saint George (the Popham Colony), at the mouth of the Kennebec River (Colony, now Phippsburg, abandoned 1608)
- Popham colonists build Maine's first ocean–going ship, a 30-ton pinnace, The Virginia, which crosses the Atlantic at least twice and sails along the Maine coast in 1608 and 1609.
- Father Pierre Baird (1565–1622), a French Jesuit, establishes Indian mission at Indian Island on Penobscot River.
- John Smith (1580–1631) visits Maine, publishes Description of New England in 1616, which encourages English settlement in Maine
- "The Great Dying." More than 75 percent of Maine's Indians die of European diseases
- Trading posts and settlements established in southern coastal Maine
- Sir Ferdinando Gorges (c.1565–1647) and John Mason granted rights to Maine and New Hampshire. Gorges gives his area the name "Maine"
- One of earliest known sawmills in America built on Piscataqua River in Berwick
- Maine's first court convenes at Saco (a Massachusetts Bay Colony court)
- Massachusetts Bay Colony annexes southwestern Maine for strategic importance as first line of defense against French and Indians for control of North America. Locals dub it "Submission to Massachusetts"
- Area of Eastern Maine known as Pentagoet granted to French; British reclaim it in 1779
- Massachusetts buys the deed to Maine from Gorges heirs; "submission" of Maine creates resentment toward Massachusetts
- Western Maine Indians raid English settlements in Maine during King Philip's War; eastern tribes join in later