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 Viceroy 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.

The federal government recognizes Pittsburgh as the starting point for the Lewis and Clark Expedition. Preparations began in Pittsburgh in 1803 when Meriwether Lewis purchased a keelboat that would later be used to ascend the Missouri River.

The War of 1812 cut off the supply of British goods, stimulating American industry. By 1815, Pittsburgh was producing significant quantities of iron, brass, tin, and glass. On March 18, 1816, the 46-year-old local government became a city. It was served by numerous river steamboats that increased trading traffic on the rivers.

In the 1830s, many Welsh people from the Merthyr steelworks immigrated to the city following the aftermath of the Merthyr Rising. By the 1840s, Pittsburgh was one of the largest cities west of the Allegheny Mountains. The Great Fire of Pittsburgh destroyed over a thousand buildings in 1845. The city rebuilt with the aid of Irish immigrants who came to escape the Great Famine. By 1857, Pittsburgh's 1,000 factories were consuming 22 million coal bushels yearly. Coal mining and iron manufacturing attracted waves of European immigrants to the area, with the most coming from Germany.

Because Pennsylvania had been established as a free state after the Revolution, enslaved African Americans sought freedom here through escape as refugees from the South, or occasionally fleeing from travelers they were serving who stayed in the city. There were active stations of the Underground Railroad in the city, and numerous refugees were documented as getting help from station agents and African-American workers in city hotels. The Drennen Slave Girl walked out of the Monongahela House in 1850, apparently to freedom. The Merchant's Hotel was also a place where African-American workers would advise slaves the state was free and aid them in getting to nearby stations of the Underground Railroad. Sometimes refugee slaves from the South stayed in Pittsburgh, but other times they continued North, including into Canada. Many slaves left the city and county for Canada after Congress passed the 1850 Fugitive Slave Act, as it required cooperation from law enforcement even in free states and increased penalties. From 1850 to 1860, the black population in Allegheny County dropped from 3,431 to 2,725 as people headed to more safety in Canada.

The American Civil War boosted the city's economy with increased iron and armament demand by the Union. Andrew Carnegie began steel production in 1875 at the Edgar Thomson Steel Works in North Braddock, Pennsylvania, which evolved into the Carnegie Steel Company. He adopted the Bessemer process to increase production. Manufacturing was key to growth of Pittsburgh and the surrounding region. Railroad lines were built into the city along both rivers, increasing transportation access to important markets.

n 1901, J. P. Morgan and attorney Elbert H. Gary merged Carnegie Steel Company and several other companies into U.S. Steel. By 1910, Pittsburgh was the nation's eighth-largest city, accounting for between one-third and one-half of national steel output.

The city's population swelled to more than a half million, attracting numerous European immigrants to its industrial jobs. By 1940, non-Hispanic whites were 90.6% of the city's population. Pittsburgh also became a main destination of the African-American Great Migration from the rural South during the first half of the 20th century. Limited initially by discrimination, some 95% percent of the men became unskilled steel workers.

During World War II, demand for steel increased and area mills operated 24 hours a day to produce 95 million tons of steel for the war effort.This resulted in the highest levels of air pollution in the city's almost century of industry. The city's reputation as the "arsenal of democracy" was being overshadowed by James Parton's 1868 observation of Pittsburgh being "hell with the lid off."

Following World War II, the city launched a clean air and civic revitalization project known as the "Renaissance," cleaning up the air and the rivers. The "Renaissance II" project followed in 1977, focused on cultural and neighborhood development. The industrial base continued to expand through the 1970s, but beginning in the early 1980s both the area's steel and electronics industries imploded during national industrial restructuring. There were massive layoffs from mill and plant closures.

In the later 20th century, the area shifted its economic base to education, tourism, and services, largely based on healthcare/medicine, finance, and high technology such as robotics. Although Pittsburgh successfully shifted its economy and remained viable, the city's population has never rebounded to its industrial-era highs. While 680,000 people lived in the city proper in 1950, a combination of suburbanization and economic turbulence resulted in a decrease in city population, even as the metropolitan area population increased again.

During the late 2000s recession, Pittsburgh was economically strong, adding jobs when most cities were losing them. It was one of the few cities in the United States to see housing property values rise. Between 2006 and 2011, the Pittsburgh metropolitan statistical area (MSA) experienced over 10% appreciation in housing prices, the highest appreciation of the largest 25 metropolitan statistical areas in the United States, with 22 of the largest 25 metropolitan statistical areas experiencing depreciations in housing values.