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18th century

The first known European to enter the region was the French explorer Robert de La Salle from Quebec during his 1669 expedition down the Ohio River. European pioneers, primarily Dutch, followed in the early 18th century. Michael Bezallion was the first to describe the forks of the Ohio in a 1717 manuscript, and later that year European fur traders established area posts and settlements.

In 1749, French soldiers from Quebec launched an expedition to the forks to unite Canada with French Louisiana via the rivers. During 1753–1754, the British hastily built Fort Prince George before a larger French force drove them off. The French built Fort Duquesne based on LaSalle's 1669 claims. The French and Indian War, the North American front of the Seven Years' War, began with the future Pittsburgh as its center. British General Edward Braddock was dispatched with Major George Washington as his aide to take Fort Duquesne. The British and colonial force were defeated at Braddock's Field. General John Forbes finally took the forks in 1758. He began construction on Fort Pitt, named after William Pitt the Elder, while the settlement was named "Pittsborough".

During Pontiac's War, a loose confederation of Native American tribes laid siege to Fort Pitt in 1763; the siege was eventually lifted after Colonel Henry Bouquet defeated a portion of the besieging force at the Battle of Bushy Run. Bouquet strengthened the defenses of Fort Pitt the next year.

During this period, the powerful nations of the Iroquois Confederacy, based in New York, had maintained control of much of the Ohio Valley as hunting grounds by right of conquest after defeating other tribes. By the terms of the 1768 Treaty of Fort Stanwix, the Penns were allowed to purchase the modern region from the Iroquois. A 1769 survey referenced the future city as the "Manor of Pittsburgh". Both the Colony of Virginia and the Province of Pennsylvania claimed the region under their colonial charters until 1780, when they agreed under a federal initiative to extend the Mason–Dixon line westward, placing Pittsburgh in Pennsylvania. On March 8, 1771, Bedford County, Pennsylvania was created to govern the frontier.

On April 16, 1771, the city's first civilian local government was created as Pitt Township. William Teagarden was the first constable, and William Troop was the first clerk.

Following the American Revolution, the village of Pittsburgh continued to grow. One of its earliest industries was boat building for settlers of the Ohio Country. In 1784, Thomas Vickroy completed a town plan which was approved by the Penn family attorney. Pittsburgh became a possession of Pennsylvania in 1785. The following year, the Pittsburgh Post-Gazette was started, and in 1787, the Pittsburgh Academy was chartered. Unrest during the Whiskey Rebellion of 1794 resulted in federal troops being sent to the area. By 1797, glass manufacture began, while the population grew to around 1,400. Settlers arrived after crossing the Appalachian Mountains or through the Great Lakes. Fort Pitt (now Pittsburgh) at the source of the Ohio River became the main base for settlers moving into the Northwest Territory.