The area of the Ohio headwaters was inhabited by the Shawnee and several other settled groups of native Americans.  The first European was the French trader Robert de La Salle in his 1669 expedition down the Ohio River from Lake Ontario and Quebec.   European pioneers, primarily Dutch, followed in the early 18th century.  In 1717 European traders first became established in the area.   In 1749, French soldiers from Quebec launched a serious expedition to the forks to unite Canada with French Louisiana via the rivers.  The French and Indian War began with the future Pittsburgh as its center and in 1758 the French surrendered the forks.  Construction began on Fort Pitt, named after British Secretary of State and soon-to-be Prime Minister William Pitt the Elder while the settlement was named "Pittsborough". 

The War of 1812 cut off the supply of British goods, stimulating American manufacture.  By 1815, Pittsburgh was producing significant quantities of iron, brass, tin and glass and in March, 1816 the 46 year old local government became a city.  By the 1840s, Pittsburgh was one of the largest cities west of the Allegheny Mountains.  The American Civil War boosted the city's economy with increased iron and armament production.  By 1911 Pittsburgh was the nation's 8th largest city accounting for between a third and a half of national steel output.  The city's population swelled to over a half million with European immigration via Ellis Island. By 1940, non-Hispanic whites were 90.6% of the city's population.  Pittsburgh was a main destination of the African-American Great Migration with 95% percent becoming unskilled steel workers.  World War II saw area mills operate 24 hours a day to produce 95 million tons of steel, but also recorded the highest levels of air pollution in its 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 the war, the city launched a clean air and civic revitalization project known as the "Renaissance" which was followed by a project in 1977 focusing on cultural and neighborhood development.  Beginning in the early 1980s both the area's steel and electronics industries imploded, with massive layoffs from mill and plant closures.

In the latter 20th century the area shifted its economic base to education, tourism, and services, largely based on healthcare, finance and high technology such as robotics. Although Pittsburgh successfully shifted its economy and remained viable, the city's population 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 caused a decrease in city population.