At the time of the arrival of the Europeans in the 1600s, both Iroquoi and Algonquian peoples already lived in the Credit River Valley area. One of the First Nations groups the traders found around the River area was called the Mississaugas, a tribe originally from Lake Huron. By 1700 the Mississaugas had driven away the Iroquois.

In 1805, government officials from York, as Toronto was then called, bought 84,000 acres of the Mississauga Tract and in 1806 the area was opened for settlement. The various communities settled include: Clarkson, Cooksville, Dixie, Erindale (called Springfield until 1890), Port Credit, Sheridan, and Summerville. This region eventually became known as the Toronto Township, formed on August 2, 1805.

After the land was surveyed, much of it was given by the Crown in the form of land grants to United Empire Loyalists who emigrated from the US. More than a dozen small communities grew in this area, most of which were located near natural resources, waterways for industry and fishing, and routes leading into York.

In 1873, in light of the continued growth seen in this area, the Toronto Township Council was formed to oversee the affairs of the various villages that were unincorporated at that time. The Council's responsibilities included road maintenance, the establishment of a police force, and mail delivery service.

In 1820, a second purchase was made and additional settlements were established. This led to the eventual displacement of the Mississauga peoples and, in 1847, they were relocated to a reserve in the Grand River Valley near present-day Hagersville. Except for small villages, most of present-day Mississauga was agricultural land, including fruit growing orchards through much of the 19th and first half of the 20th century. Toronto residents would travel to the township to pick fruits and garden vegetables.

Cottages were constructed along Lake Ontario in the 1920's as weekend getaway houses for weary city dwellers. Malton Airport opened in 1937, which would later become Canada's busiest airport, Toronto Pearson International Airport.

The Queen Elizabeth Way highway, one of the first controlled access highways in the world, opened in 1939. The first suburban developments occurred around the same time. Development in general moved north and west from there; large scale developments such as in Meadowvale and Erin Mills sprung up in the 1960s and 70s.

With the exception of Port Credit and Streetsville, the township settlements were amalgamated by a somewhat unpopular provincial decree in 1968 to form the Town of Mississauga. In 1974, both were annexed and Mississauga became a city. That year, the sprawling Square One shopping center opened.

The name "Mississauga" is to many Canadians associated with a major rail disaster that happened on November 10, 1979, when a 106 car freight train carrying explosive and poisonous chemicals was derailed at the intersection of Mavis Road and Dundas in Mississauga.

The resulting fire was allowed to burn itself out, but a ruptured chlorine tank was the main cause for concern. With the possibility of a deadly cloud of chlorine gas spreading through suburban Mississauga, 218,000 people were evacuated. Within a few days Mississauga was practically a ghost town, later when the mess had been cleared and the danger neutralized residents were allowed to return to their homes.

At the time, it was the largest peacetime evacuation in North American history. Due to the speed and efficiency in which it was conducted, many cities later studied and modeled their own emergency plans after Mississauga's.